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(Updated 7/20/04)

Danysz W.
CX-516 Cortex pharmaceuticals.
Curr Opin Investig Drugs 2002 Jul;3(7):1081-8
"CX-516 is one of a series of AMPA modulators under development by Cortex, in collaboration with Shire and Servier, for the potential treatment of Alzheimer's disease (AD), schizophrenia and mild cognitive impairment (MCI) [234221]. By June 2001, CX-516 was in phase II trials for both schizophrenia and attention deficit hyperactivity disorder (ADHD) [412513]. A phase II trial in fragile X syndrome and autism was expected to start in May 2002 [449861]. In October 2001, Cortex was awarded a Phase II SBIR grant of $769,818 from the National Institutes of Mental Health to investigate the therapeutic potential of AMPAkines in schizophrenia. This award was to support a phase IIb study of CX-516 as a combination therapy in schizophrenia patients concomitantly treated with olanzapine. The trial was to enroll 80 patients and employ a randomized, double-blind, placebo-controlled design in which the placebo group was to receive olanzapine plus placebo and the active group was to receive olanzapine plus CX-516 [425982]. In April 2000, Shire and Cortex signed an option agreement in which Shire was to evaluate CX-516for the treatment of ADHD. Under the terms of the agreement, Shire would undertake a double-blind, placebo-controlled evaluation of CX-516 involving ADHD patients. If the study proved effective, Shire would have the right to convert its option into an exclusive worldwide license for the AMPAkines for ADHD under a development and licensing agreement. Should Shire elect to execute this agreement, Shire would bear all future developmental costs [363618]. By February 2002, Cortex and Servier had revealed their intention to begin enrolment for an international study of an AMPAkine compound as a potential treatment for MCI in the near future. Assuming enrollment proceeded as anticipated, results were expected during the second quarter of 2003 [439301]. By May 2002, phase II trials were underway [450134]. In March 2002, Cortex was awarded extended funding under the University of California BioSTAR projectfor the research project: 'Ampakine modulation of brain neurotrophin expression: a novel therapeutic strategy'. This funding was expected to amount to $193,000 over a two-year period [444872]." [Abstract]

Johnson SA, Simmon VF.
Randomized, double-blind, placebo-controlled international clinical trial of the Ampakine CX516 in elderly participants with mild cognitive impairment: a progress report.
J Mol Neurosci 2002 Aug-Oct;19(1-2):197-200
"This progress report briefly describes the rationale and study design for the first cross-national clinical study of a positive AMPA-type glutamate receptor modulator in subjects with mild cognitive impairment (MCI). The study medication for the double-blind, placebo-controlled trial, the AMPAKINE CX516, represents a novel pharmacological approach to the treatment of memory disorders. Previous preclinical and pilot clinical studies have shown that CX516 has the ability to enhance memory and cognition. Design of the trial, including outcome measures and inclusion criteria, was aided by an international panel of experts in the newly emerging field of MCI." [Abstract]

Ingvar M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G.
Enhancement by an ampakine of memory encoding in humans.
Exp Neurol 1997 Aug;146(2):553-9
"Acentrally active drug that enhances AMPA receptor-mediated currents was tested for its effects on memory in humans. Evidence for a positive influence on encoding was obtained in four tests: (i) visual associations, (ii) recognition of odors, (iii) acquisition of a visuospatial maze, and (iv) location and identity of playing cards. The drug did not improve scores in a task requiring cued recall of verbal information. The selectivity of drug effects on memory was confirmed using tests of visual recognition, motor performance, and general intellectual functioning. These results suggest that positive modulators of AMPA receptors selectively improve at least some aspects of memory." [Abstract]

Lynch G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R.
Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans.
Exp Neurol 1997 May;145(1):89-92
"Elderly subjects (65-76 years) were tested for recall of nonsense syllables prior to and after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine (CX516), a centrally active drug that enhances currents mediated by AMPA-type glutamate receptors. A significant and positive drug effect was found for delayed (5 min) recall at 75 min posttreatment; average scores for the highest dose group were more than twofold greater than for the placebo group. The drug had no evident influence on heart rate or self-assessment of several psychological variables." [Abstract]

Lynch G, Kessler M, Rogers G, Ambros-Ingerson J, Granger R, Schehr RS.
Psychological effects of a drug that facilitates brain AMPA receptors.
Int Clin Psychopharmacol 1996 Mar;11(1):13-9
"The effects of 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516), a centrally active compound that facilitates AMPA receptor-mediated synaptic responses, were tested in human subjects. Separate tests of delayed recall were given prior to and nearly 3 h after administration of placebo (n = 12) or drug (n = 36). Control subjects exhibited poorer performance in the second session than in the first while subjects given 600-1200 mg of the drug did not. There were no pre- vs post-treatment differences in immediate recall in either group. The drug did not reliably affect self-assessment scores for any of several psychological variables but did disrupt the normally present correlations for within-subject changes in the variables. These results suggest that AMPA receptor modulators may (1) improve memory under some circumstances and (2) produce psychological effects that are subtle or not related to specific mood states." [Abstract]

Larson J, Lieu T, Petchpradub V, LeDuc B, Ngo H, Rogers GA, Lynch G.
Facilitation of olfactory learning by a modulator of AMPA receptors.
J Neurosci 1995 Dec;15(12):8023-30
"The effects of a benzoyl-piperidine drug (BDP) that facilitates AMPA receptor-mediated synaptic responses were tested on the acquisition and retention of long-term memory at dosages that had no detectable effects on a variety of performance measures. BDP-12 produced a dose-dependent suppression of exploratory activity in rats with statistically reliable effects occurring at 50 mg/kg (i.p.). The drug had no effects on balance beam performance at 30 mg/kg but at 45 mg/kg reduced the number of crossings made within a session; it did not, however, affect the time required to perform a traversal. The performance of well-trained rats presented with a familiar pair of odors (correct and incorrect) was not not detectably altered by BDP-12 at 30 mg/kg; however, the number of correct responses made in a five-trial test was reduced at 45 mg/kg. These results indicate that the AMPA receptor modulator at 30 mg/kg has little influence on arousal, motivation, sensori-motor processing, and attention; higher dosages cause a depression of learned and unlearned prepotent responses. The effects of the lower concentration were tested on two-odor discrimination learning in rats that had extensive training on the task. The animals (n = 20) were given three or five acquisition trials with novel odor pairs immediately after an injection of drug or vehicle and then tested 1-3 d later for retention in five unrewarded probe trials. Retention performance was not significantly better than chance 52.6 +/- 4.5% correct) for odors learned on vehicle injection days but was well above chance for odors learned on drug injection days (70.6 +/- 4.2% correct). Within-subject comparisons confirmed the memory enhancing effect of BDP-12 (p < 0.01). Analyses of performance during five training trials indicated that the rats made more correct responses on days on which they were given the drug than on days on which they were injected with vehicle (p < 0.02). Within-subject differences in acquisition were correlated with differences in retention (r = 0.70). There were no evident effects of the drug on response latencies during acquisition. These results suggest that AMPA receptor modulators reduce the amount of training needed for the formation of long-term memory and do so at dosages which have little effect on variables that secondarily influence acquisition. Possible reasons for this selectivity are discussed." [Abstract]

Staubli U, Izrael Z, Xu F.
Remembrance of odors past: enhancement by central facilitation of AMPA receptors.
Behav Neurosci 1996 Oct;110(5):1067-73
"Pharmacological facilitation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptor has recently been demonstrated to enhance synaptic responses, promote long-term potentiation (LTP) induction in freely moving rats, and facilitate learning and retention of information. The present study verifies and extends the behavioral action of allosteric AMPA receptor modulation by showing that the benzoyl-piperidine compound BDP-12 promotes retention of olfactory and transient spatial memory in a dose-dependent fashion; is only effective when given before but not after training, consistent with the hypothesis that glutamatergic facilitation enhances information encoding by means of action on the machinery involved in LTP induction; and, following suboptimal training in a paradigm of enduring memory, prolongs the ability of rats to retain odors by extending the decay of weak memory traces." [Abstract]

Yamada KA.
Modulating excitatory synaptic neurotransmission: potential treatment for neurological disease?
Neurobiol Dis 1998 Aug;5(2):67-80
"Excitatory neurotransmission at many CNS synapses depends upon AMPA-type glutamate receptors. Derangements in AMPA receptor-mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Drugs that positively modulate AMPA receptors by reducing AMPA receptor desensitization and/or slowing AMPA receptor deactivation, such as thiazide derivative (cyclothiazide, diazoxide, IDRA 21) and benzoylpiperidine derivatives (1-BCP, CX516, aniracetam), facilitate AMPA receptor-mediated processes and may have beneficial therapeutic effects. For example, AMPA modulators facilitate long-term potentiation, which may be important for memory storage, and facilitate memory encoding in behavioral experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer's disease." [Abstract]

Arai AC, Xia YF, Suzuki E.
Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus.
Neuroscience. 2004;123(4):1011-24.
"Prior studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-D-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus.Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding." [Abstract]

Arai, Amy C., Kessler, Markus, Rogers, Gary, Lynch, Gary
Effects of the Potent Ampakine CX614 on Hippocampal and Recombinant AMPA Receptors: Interactions with Cyclothiazide and GYKI 52466
Mol Pharmacol 2000 58: 802-813
"R,S-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor up-modulators of the benzamide type ("ampakines") have previously been shown to enhance excitatory synaptic transmission in vivo and in vitro and AMPA receptor currents in excised patches. The present study analyzed the effects of an ampakine (CX614; 2H,3H, 6aH-pyrrolidino[2",1"-3',2']1,3-oxazino[6',5'-5,4]benz o[e]1, 4-dioxan-10-one) that belongs to a benzoxazine subgroup characterized by greater structural rigidity and higher potency. CX614 enhanced the size (amplitude and duration) of field excitatory postsynaptic potentials in hippocampal slices and autaptically evoked excitatory postsynaptic currents in neuronal cultures with EC(50) values of 20 to 40 microM. The compound blocked desensitization (EC(50) = 44 microM) and slowed deactivation of responses to glutamate by a factor of 8.4 in excised patches. Currents through homomeric, recombinant AMPA receptors were enhanced with EC(50) values that did not differ greatly across GluR1-3 flop subunits (19-37 microM) but revealed slightly lower potency at corresponding flip variants. Competition experiments using modulation of [(3)H]fluorowillardiine binding suggested that CX614 and cyclothiazide share a common binding site but cyclothiazide seems to bind to an additional site not recognized by the ampakine. CX614 did not reverse the effect of GYKI 52466 on responses to brief glutamate pulses, which indicates that they act through separate sites, a conclusion that was confirmed in binding experiments. In sum, these results extend prior evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation, and that their effects are exerted through sites that are only in part shared with other modulators." [Full Text]

Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM
Chronic elevation of brain-derived neurotrophic factor by ampakines.
J Pharmacol Exp Ther. 2003 Oct;307(1):297-305. Epub 2003 Jul 31.
"The ampakine CX614 positively modulates alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor (BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases BDNF gene expression but with time, mRNA levels fall despite the continued presence of active drug. The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h) treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546) did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity. Finally, using a "24-h on/24-h off" CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF mRNA was induced with each ampakine application, and elevated BDNF protein levels were maintained through 5 days in vitro. These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins." [Abstract]

Lauterborn, Julie C., Lynch, Gary, Vanderklish, Peter, Arai, Amy, Gall, Christine M.
Positive Modulation of AMPA Receptors Increases Neurotrophin Expression by Hippocampal and Cortical Neurons
J. Neurosci. 2000 20: 8-21
"This study investigated whether positive modulators of AMPA-type glutamate receptors influence neurotrophin expression by forebrain neurons. Treatments with the ampakine CX614 markedly and reversibly increased brain-derived neurotrophic factor (BDNF) mRNA and protein levels in cultured rat entorhinal/hippocampal slices. Acute effects of CX614 were dose dependent over the range in which the drug increased synchronous neuronal discharges; threshold concentrations for acute responses had large effects on mRNA content when applied for 3 d. Comparable results were obtained with a second, structurally distinct ampakine CX546. Ampakine-induced upregulation was broadly suppressed by AMPA, but not NMDA, receptor antagonists and by reducing transmitter release. Antagonism of L-type voltage-sensitive calcium channels blocked induction in entorhinal cortex but not hippocampus. Prolonged infusions of suprathreshold ampakine concentrations produced peak BDNF mRNA levels at 12 hr and a return to baseline levels by 48 hr. In contrast, BDNF protein remained elevated throughout a 48 hr incubation with the drug. Nerve growth factor mRNA levels also were increased by ampakines but with a much more rapid return to control levels during chronic administration. Finally, intraperitoneal injections of CX546 increased hippocampal BDNF mRNA levels in aged rats and middle-aged mice. The present results provide evidence of regional differences in mechanisms via which activity regulates neurotrophin expression. Moreover, these data establish that changes in synaptic potency produce sufficient network level physiological effects for inducing neurotrophin genes, indicate that the response becomes refractory during prolonged ampakine exposure, and raise the possibility of using positive AMPA modulators to regulate neurotrophin levels in aged brain." [Full Text]

Black MD, Wotanis J, Schilp DE, Hanak SE, Sorensen SM, Wettstein JG.
Effect of AMPA receptor modulators on hippocampal and cortical function.
Eur J Pharmacol 2000 Apr 7;394(1):85-90
"Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA." [Abstract]

Arai A, Lynch G.
The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization.
Brain Res 1998 Jul 20;799(2):230-4
"Relationships between the kinetic properties of AMPA receptors and the decay phase of fast excitatory transmission were investigated using modulatory drugs. The benzothiadiazide compound cyclothiazide blocked receptor desensitization in patches excised from hippocampus but had only a weak influence on receptor deactivation, i.e., on the decay of responses produced by a 1-ms pulse of glutamate. The ampakine drug CX516 (BDP-12) produced an opposite pattern of effects: a fourfold slowing of deactivation with little change in desensitization. A structurally related drug (CX554 or BDP-20) had prominent effects on both desensitization and deactivation. The halfwidth of field EPSPs measured in the CA1 region of hippocampal slices increased 50-100% in the presence of CX516 or CX554 but by less than 15% at concentrations of cyclothiazide that fully blocked desensitization in patch experiments. These results indicate that receptor deactivation plays a substantially greater role than receptor desensitization in determining the duration of synaptic responses." [Abstract]

Brent D. Holst, Peter W. Vanderklish, Leslie A. Krushel, Wei Zhou, Ronald B. Langdon, John R. McWhirter, Gerald M. Edelman, and Kathryn L. Crossin
Allosteric modulation of AMPA-type glutamate receptors increases activity of the promoter for the neural cell adhesion molecule, N-CAM
PNAS 95: 2597-2602, 1997.
"To study regulation in vivo of the promoter for the neural cell adhesion molecule, N-CAM, we have used homologous recombination to insert the bacterial lacZ gene between the transcription and translation initiation sites of the N-CAM gene. This insertion disrupts the gene and places the expression of beta-galactosidase under the control of the N-CAM promoter. Animals homozygous for the disrupted allele did not express N-CAM mRNA or protein, but the pattern of beta-galactosidase expression in heterozygous and homozygous embryos was similar to that of N-CAM mRNA in wild-type animals. The homozygotes exhibited many of the morphological abnormalities observed in previously reported N-CAM knockout mice, with the exception that hippocampal long-term potentiation in the Schaffer collaterals was identical in homozygous, heterozygous, and wild-type animals. Heterozygous mice were used to examine the regulation of the N-CAM promoter in response to enhanced synaptic transmission. Treatment of the mice with an ampakine, an allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that enhances normal glutamate-mediated synaptic transmission, increased the expression of beta-galactosidase in vivo as well as in tissue slices in vitro. Similar treatments also increased the expression of N-CAM mRNA in the heterozygotes. The effects of ampakine in slices were strongly reduced in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. Taken together, these results indicate that facilitation of AMPA receptor-mediated transmission leads to activation of the N-CAM promoter and provide support for the hypothesis that N-CAM synthesis is regulated in part by synaptic activity." [Full Text]

Arai A, Kessler M, Rogers G, Lynch G.
Effects of a memory-enhancing drug on DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents and synaptic transmission in hippocampus.
J Pharmacol Exp Ther 1996 Aug;278(2):627-38
"The benzoylpiperidine drug BDP-12 (1-(quinoxalin-6-ylcarbonyl)piperidine) enhances the encoding of transient and stable forms of memory by rats. Results reported here show that the drug increases fast, excitatory (glutamatergic) synaptic responses in hippocampal slices by about 50% with an EC50 of 170 microM. Analyses with polysynaptic responses indicated that the drug has a facilitatory action at concentrations as low as 12.5 microM. BDP-12 at 1 mM did not change the resting membrane potential, input resistance or spiking threshold and it did not alter monosynaptic potentials mediated by gamma-aminobutyric acid (GABA) receptors; it did, however, enhance disynaptic inhibitory responses. In membrane patches excised from hippocampal neurons, BDP-12 at moderate concentrations (50 microM) increased the steady-state currents mediated by DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and slowed the rate at which the receptors desensitize, with a much larger effect on the former; the drug delayed the closing of the AMPA receptor channel after 1-msec agonist pulses. BDP-12 had no detectable effect on [3H]AMPA binding affinity. A related and more potent analog produced a different pattern of results in that it had about equal effects on steady-state currents and desensitization rates and significantly increased binding to AMPA receptors. These results indicate that the benzoylpiperidine family of modulators has functionally distinct subclasses. The findings also establish that BDP-12: 1) enhances synaptic responses in the same concentration range at which it alters AMPA receptor kinetics, 2) has a lower apparent threshold for effects on complex network operations than on monosynaptic transmission, 3) does not directly influence inhibitory responses and 4) is likely to modulate AMPA receptors on interneurons as well as on pyramidal neurons."

Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G.
A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia.
J Clin Psychopharmacol 2001 Oct;21(5):484-7
"CX516, a positive modulator of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, improves performance in tasks requiring learning and memory in animals. CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N = 6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated with moderate to large, between-group effect sizes compared with placebo, representing improvement in measures of attention and memory. These preliminary results suggest that CX516 and other "ampakines" hold promise for the treatment of schizophrenia." [Abstract]

Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, Weinberger DR.
Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series.
Schizophr Res 2002 Oct 1;57(2-3):221-6
"We used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited." [Abstract]

Johnson, Steven A., Luu, Nguyen T., Herbst, Todd A., Knapp, Richard, Lutz, David, Arai, Amy, Rogers, Gary A., Lynch, Gary
Synergistic Interactions between Ampakines and Antipsychotic Drugs
J Pharmacol Exp Ther 1999 289: 392-397
"Tests were made for interactions between antipsychotic drugs and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors ("ampakines"). Typical and atypical antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the effects of near or even subthreshold doses of the antipsychotics were greatly enhanced by the ampakines. Interactions between the ampakine CX516 and low doses of different antipsychotics were generally additive and often synergistic. The ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the interaction between the different pharmacological classes was selective. These results suggest that positive modulators of cortical glutamatergic systems may be useful adjuncts in treating schizophrenia." [Full Text]

Lynch G.
Memory and the brain: unexpected chemistries and a new pharmacology.
Neurobiol Learn Mem 1998 Jul-Sep;70(1-2):82-100
"Efforts to characterize long-term potentiation (LTP) and to identify its substrates have led to the discovery of novel synaptic chemistries, computational algorithms, and, most recently, pharmacologies. Progress has also been made in using LTP to develop a "standard model" of how unusual, but physiologically plausible, levels of afferent activity create lasting changes in the operating characteristics of synapses in the cortical telencephalon. Hypotheses of this type typically distinguish induction, expression, and consolidation stages in the formation of LTP. Induction involves a sequence consisting of theta-type rhythmic activity, suppression of inhibitory currents, intense synaptic depolarization, NMDA receptor activation, and calcium influx into dendritic spines. Calcium-dependent lipases, kinases, and proteases have been implicated in LTP induction. Regarding the last group, it has been recently reported that theta pattern stimulation activates calpain and that translational suppression of the protease blocks potentiation. It is thus likely that proteolysis is readily driven by synaptic activity and contributes to structural reorganization. LTP does not interact with treatments that affect transmitter release, has a markedly differential effect on the currents mediated by colocalized AMPA vs NMDA synaptic receptors, changes the waveform of the synaptic current, modifies the effects of drugs that modulate AMPA receptors, and is sensitive to the subunit composition of those receptors. These results indicate that LTP is expressed by changes in AMPA receptor operations. LTP is accompanied by modifications in the anatomy of synapses and spines, something which accounts for its extreme duration (weeks). As with various types of memory, LTP requires about 30 min to consolidate (become resistant to disruption). Consolidation involves adhesion chemistries and, in particular, activation of integrins, a class of transmembrane receptors that control morphology in numerous cell types. Platelet activating factor and adenosine may contribute to consolidation by regulating the engagement of latent integrins. How consolidation stabilizes LTP expression is a topic of intense investigation but probably involves modifications to one or more of the following: membrane environment of AMPA receptors; access of regulatory proteins (e.g., kinases, proteases) to the receptors; receptor clustering; and space available for receptor insertion. Attempts to enhance LTP have focused on the induction phase and resulted in a class of centrally active drugs ("ampakines") that positively modulate AMPA receptors. These compounds promote LTP in vivo and improve the encoding of variety of memory types in animals. Positive results have also been obtained in preliminary studies with humans." [Abstract]

Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL.
Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity.
Nature. 2000 Jun 22;405(6789):955-9.
"Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history." [Abstract]

Hampson, Robert E., Rogers, Gary, Lynch, Gary, Deadwyler, Sam A.
Facilitative Effects of the Ampakine CX516 on Short-Term Memory in Rats: Enhancement of Delayed-Nonmatch-to-Sample Performance
J. Neurosci. 1998 18: 2740-2747
"Ampakines are a family of drugs that selectively increase AMPA receptor-gated currents and improve performance on several behavioral tasks. This report describes evidence that ampakines cause a cumulative enhancement of performance in a spatial short-term memory task (Deadwyler et al., 1996). Two groups of rats were trained on a spatial variant of the delayed-nonmatch-to-sample (DNMS) paradigm. One group (n = 12) received the ampakine CX516 (Cortex Pharmaceuticals) alternated with vehicle for 17 consecutive days and then only vehicle for an additional 7 d. The second group (n = 6) received only vehicle injections over the same number of days. CX516 improved performance within sessions, particularly on trials with delays of 6-35 sec. In 9 of 12 rats, the positive effect of the drug was also present on nondrug days between CX516 administration and after cessation of CX516 injections. The animals that received only vehicle injections showed no improvement in DNMS performance over the entire 32 d of testing. Three of the 12 animals given CX516 did not exhibit "carryover" effects of the drug to the intervening (vehicle only) test sessions, but nonetheless exhibited superior performance during the first half of the session on days in which the ampakine was administered. Evaluation of errors suggests that the ampakine eliminated the necessity for a shift in response strategy that produced proactive interference on the following trial. Hippocampal involvement in these ampakine effects is discussed as a prelude to the second article in the series (Hampson et al., 1998)." [Full Text]

Hampson, Robert E., Rogers, Gary, Lynch, Gary, Deadwyler, Sam A.
Facilitative Effects of the Ampakine CX516 on Short-Term Memory in Rats: Correlations with Hippocampal Neuronal Activity
J. Neurosci. 1998 18: 2748-2763
"In the companion article (Hampson et al., 1998), the ampakine CX516 (Cortex Pharmaceuticals) was shown to produce a marked facilitation of performance of a spatial delayed-nonmatch-to-sample (DNMS) task in rats. Injections of the drug before each daily session produced a marked and progressive improvement in performance at longer delays (>5 sec) that persisted for 7 d after drug treatment was terminated. In most animals (n = 9) the increase in performance carried over to the intervening vehicle for days, whereas in others (n = 3) the effects dissipated within the session according to the pharmacological half-life of CX516. In this article we report firing correlates of simultaneously recorded cells in the CA1 and CA3 fields of the hippocampus over the period in which DNMS performance was facilitated by CX516. Sample and Delay period firing was enhanced by 100-350% under CX516 and increased progressively over days as did DNMS performance. The firing increases were restricted to correct trials only and were largest on trials with long delays. Firing in the intertrial interval was also altered, but in a manner consistent with a previously demonstrated reduction in between-trial proactive interference by CX516. Finally, in animals in which the effects of CX516 were restricted to when the drug was actually present (i.e., no carryover effects), increased cell firing also paralleled the time course of the performance increase. Results are discussed with respect to the actions of ampakines on hippocampal cellular and synaptic processes that underlie DNMS performance." [Full Text]

Arai AC, Xia YF, Rogers G, Lynch G, Kessler M.
Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action.
J Pharmacol Exp Ther 2002 Dec;303(3):1075-85
"CX516 (BDP-12) and CX546, two first-generation benzamide-type AMPA receptor modulators, were compared with regard to their influence on AMPA receptor-mediated currents, autaptic responses in cultured hippocampal neurons, hippocampal excitatory postsynaptic currents, synaptic field potentials, and agonist binding. The two drugs exhibited comparable potencies in most tests but differed in their efficacy and in their relative impact on various response parameters. CX546 greatly prolonged the duration of synaptic responses, and it slowed 10-fold the deactivation of excised-patch currents following 1-ms pulses of glutamate. The effects of CX516 on those measures were, by comparison, small; however, the drug was equally or more efficacious than CX546 in increasing the amplitude of synaptic responses. This double dissociation suggests that amplitude and duration of synaptic responses are governed by different aspects of receptor kinetics, which are differentially modified by the two drugs. These effects can be reproduced in receptor simulations if one assumes that CX516 preferentially accelerates channel opening while CX546 slows channel closing. In binding tests, CX546 caused an approximately 2-fold increase in the affinity for radiolabeled agonists, whereas CX516 was ineffective. More importantly, even millimolar concentrations of CX516 did not influence the dose-response relation for CX546, suggesting the possibility that they bind to different sites. Taken together, the evidence suggests that benzamide modulators from the Ampakine family form two subgroups with different modes and sites of action. Of these, CX516-type drugs may have the greater therapeutic utility because of their limited efficacy in prolonging synaptic responses and in attenuating receptor desensitization." [Abstract]

Nagarajan N, Quast C, Boxall AR, Shahid M, Rosenmund C.
Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546.
Neuropharmacology 2001 Nov;41(6):650-63
"Glutamate release at central synapses is transduced into a characteristic fast postsynaptic response by AMPA receptor gating and agonist affinity. The effect of two classes of modulators of AMPA receptor desensitization, the benzothiadiazides (cyclothiazide and IDRA 21) and the benzoylpiperidines (CX516 and CX546), were studied on gating kinetics of recombinant, native AMPA receptors and on synaptic currents. CX546 reduced the degree of desensitization more potently than CX516 or IDRA 21, but not as efficiently as cyclothiazide. In presence of CX516/CX546, desensitization of GluR2(flip) receptors was inhibited more than of GluR1(flip), whereas they had no effect upon response shape or conductance. CX546 increased agonist affinity threefold on nondesensitizing AMPA receptors by slowing agonist unbinding. Analysis of modulatory action suggests that, in contrast to cyclothiazide or IDRA 21, the Ampakine CX546 binds specifically to the agonist bound nondesensitized receptor, most likely acting by destabilizing the desensitized receptor conformation. All modulators tested showed higher efficiency on native receptors as compared to homomeric receptors. At the glutamatergic synapse, evoked synaptic amplitudes were weakly potentiated, while EPSC decay was slowed by nearly a factor of three in the presence of CX546 or cyclothiazide. In the presence of CX546, the current induced by short pulses of glutamate from recombinant GluR2 receptors decayed with a time course that was approximately twentyfold faster than EPSCs. The unique properties of CX546 may be beneficial for therapeutical use." [Abstract]

Suppiramaniam V, Bahr BA, Sinnarajah S, Owens K, Rogers G, Yilma S, Vodyanoy V.
Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors.
Synapse 2001 May;40(2):154-8
"Ampakines are small benzamide compounds that allosterically produce the positive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) was investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers. The drug increased the open time of AMPA-induced single channel current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the modulated currents were blocked by CNQX. It is concluded that the synaptic membrane environment is not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. They also raise the possibility that AMPA receptors are regulated by factors present in situ, thus explaining the more efficient modulatory effects of CX509 when acting on receptors removed from their synaptic location." [Abstract]

Davis CM, Moskovitz B, Nguyen MA, Tran BB, Arai A, Lynch G, Granger R.
A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors.
Psychopharmacology (Berl) 1997 Sep;133(2):161-7
"A newly developed group of benzoylpiperidine drugs that enhance AMPA-receptor-gated currents ("ampakines") has been shown to improve memory encoding in rats across a variety of experimental paradigms. The present experiments were intended to i) provide a partial profile of the behavioral changes produced by ampakines, ii) test if two ampakines (BDP-12 and BDP-20) that differ significantly in their effects on AMPA receptor kinetics produce similar behavioral profiles, and iii) determine if physiological potency is reflected in behavioral potency. BDP-20 reduced two measures of exploratory activity in aged rats but increased speed of performance in a radial maze; the drug also caused substantially improved retention of spatial information. These results are similar to those obtained with BDP-12, an analog that differs from BDP-20 in its effects on ligand binding to the AMPA receptor and on the physiological responses of the receptors to glutamate. BDP-20 was approximately ten-fold more potent in behavioral effects than BDP-12, which agrees with the relative potencies of the two drugs as assessed with excised patches and excitatory synaptic responses. These findings indicate that ampakines, though differing in their effects on AMPA-receptor-mediated responses, have similar effects at the behavioral level." [Abstract]

Munirathinam S, Rogers G, Bahr BA.
Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors elicits neuroprotection after trimethyltin exposure in hippocampus.
Toxicol Appl Pharmacol 2002 Dec 1;185(2):111-8
"The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic receptors have been linked to survival signaling, especially when the receptors are allosterically modulated by members of the Ampakine family. While increased glutamatergic communication through AMPA receptors has been shown to protect against toxic conditions that target hippocampal subfield CA1, protection in other subfields has not been shown. Accordingly, positive modulation of AMPA receptors by Ampakine compounds CX727 and CX516 was tested for effects on trimethyltin (TMT) neurotoxicity in rat hippocampal slice cultures. TMT was applied for 4 h followed by a rapid washout and antagonistic quenching of AMPA and N-methyl-D-aspartate (NMDA) receptors. After a 24-h period, the TMT-exposed slices exhibited increased levels of calpain-mediated spectrin breakdown as well as synaptic deterioration. TMT selectively targeted CA3 pyramidal neurons and dentate gyrus (DG) granule cells as evidenced by degeneration and neuronal loss. The cytoskeletal and synaptic damage was reduced when Ampakine modulation was initiated during the postinsult period. Furthermore, the extent of protection was comparable to that produced by the NMDA receptor antagonist AP5. The above results were substantiated by histological experiments, revealing that Ampakine treatment prevented TMT-induced cell loss in CA3 and DG. These results indicate that AMPA receptor signals are part of cellular repair responses following exposure to an environmental toxin." [Abstract]

Dicou E, Rangon CM, Guimiot F, Spedding M, Gressens P.
Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain.
Brain Res 2003 Apr 25;970(1-2):221-5
"Four positive modulators of AMPA-type glutamate receptors (cyclothiazide, CX614, LY404187 and S18986-1) given in acute or chronic manner exerted a neuroprotective effect in lesions induced in postnatal day 5 (P5) mice by intracerebral injection of ibotenate, an NMDA agonist. The neuroprotective effects were mediated via the MAPK pathway since coinjection of the MEK inhibitor, PD98059, blocked the neuroprotective effects. Administration of CX614 to neonatal mice was followed by upregulation of hippocampal and cortical BDNF expression." [Abstract]

Bahr BA, Bendiske J, Brown QB, Munirathinam S, Caba E, Rudin M, Urwyler S, Sauter A, Rogers G.
Survival signaling and selective neuroprotection through glutamatergic transmission.
Exp Neurol 2002 Mar;174(1):37-47
"In the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate glutamatergic neurotransmission and, when intensely activated, can induce excitotoxic cell death. In addition to their ionotropic properties, however, AMPA receptors have been functionally coupled to a variety of signal transduction events involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase (MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate signaling events in order to prevent neuronal injury and/or enhance recovery. AMPA stimulation in hippocampal slice cultures caused the selective activation of MAPK through the upstream activator MAPK kinase (MEK). Inhibition of either component of the AMPA receptor--MAPK pathway potentiated cellular damage due to serum deprivation, suggesting that this pathway facilitates compensatory signals in response to injury. Correspondingly, positive modulation of AMPA receptors with the Ampakine 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) enhanced MAPK activation and reduced the extent of synaptic and neuronal degeneration resulting from excitotoxic episodes. CX516 was neuroprotective when infused into slices either before or after the insult. The Ampakine derivative also elicited neuroprotection in an in vivo model of excitotoxicity as evidenced by reduction in lesion size and preservation of two different types of neurons. Interestingly, the AMPA receptor--MAPK pathway selectively protects against excitotoxicity since enhancing the pathway did not protect against the nonexcitotoxic, slow pathology initiated by lysosomal dysfunction. The results indicate that glutamatergic communication is important for cellular maintenance and that AMPA receptors activate survival signals to counterpoise their own excitotoxic potential." [Abstract]

Knapp RJ, Goldenberg R, Shuck C, Cecil A, Watkins J, Miller C, Crites G, Malatynska E.
Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model.
Eur J Pharmacol 2002 Apr 5;440(1):27-35
"The present study tests the activity of nootropic drugs in a behavioral test linked to depression. This test measures the reduction of submissive behavior in a competition test as the relative success of two food-restricted rats to gain access to a feeder. Nootropic drugs tested include piracetam (2-oxo-1-pyrrolidineacetamide), aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone), the Ampakine, Ampalex, 1-(quinoxalin-6-ylcarbonyl)piperidine, and analogs were compared to the antidepressants, fluoxetine ((+/-)-N-methyl-gamma-(4-[trifluoromethyl]phenoxy)-benzenepropanamine) and desimpramine (5H-dibenz[b,f]azepine-5-propanamine, 10,11-dihydro-N-methyl-, monohydrochloride), while the anxiolytic diazepam (7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one) served as a control. Drugs were given intraperitoneally for 3 weeks. The antidepressant and nootropic drugs reduced submissive behavior over time. The effect was dose dependent as measured for fluoxetine and Ampakines. The reduction of submissive behavior by Ampakines gradually faded after cessation of treatment and had a more rapid onset of activity (during the 1st week of treatment) than fluoxetine (after 2 weeks). The results suggest that Ampakines may have antidepressant activity. The potential of depression treatment with memory-enhancing drugs is hypothesized and the link between cognition and depression is discussed." [Abstract]

Baumbarger, Polly J., Muhlhauser, Mark, Zhai, Jin, Yang, Charles R., Nisenbaum, Eric S.
Positive Modulation of alpha -Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptors in Prefrontal Cortical Pyramidal Neurons by a Novel Allosteric Potentiator
J Pharmacol Exp Ther 2001 298: 86-102
"Positive modulators of glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors can enhance cognitive function in several species. The present experiments compared the actions of a novel biarylpropylsulfonamide compound, LY404187, with the prototypical benzoylpiperidine, 1-(quinoxalin-6-ylcarbonyl)-piperidine (CX516), on AMPA receptors of prefrontal cortex (PFC) pyramidal neurons. LY404187 (0.03-10 microM) selectively enhanced glutamate-evoked currents through AMPA receptor/channels of acutely isolated pyramidal neurons with considerably greater potency (EC50 = 1.3 +/- 0.3 microM) and efficacy (Emax = 45.3 +/- 8.0-fold increase) than did CX516 (EC50 = 2.8 +/- 0.9 mM; Emax = 4.8 +/- 1.4-fold increase). Both LY404187 and CX516 increased the potency of the glutamate concentration-response profile by 6- and 3-fold, respectively. Rapid perfusion experiments demonstrated that LY404187 produced a marked suppression in the magnitude but no change in the kinetics of receptor desensitization; whereas CX516 produced little change in the degree and a modest deceleration of the desensitization process. In PFC slices, both spontaneous and stimulus-evoked AMPA receptor-mediated excitatory postsynaptic potentials were enhanced by nanomolar concentrations of LY404187. Voltage-sensitive N-methyl-D-aspartate (NMDA) receptor-dependent synaptic responses also were indirectly augmented as a consequence of greater postsynaptic depolarization. Consistent with the in vitro data, LY404187 was 1000-fold more potent than CX516 in enhancing the probability of discharge of PFC neurons in response to stimulation of glutamatergic afferents from hippocampus in vivo. This potentiation by LY404187 was reduced by both selective AMPA (LY300168, 1 mg/kg, i.v.) and NMDA (LY235959, 5 mg/kg, i.v.) receptor antagonists. Collectively, these results demonstrate that LY404187 is an extremely potent and centrally active potentiator of native AMPA receptors and has a unique mechanism of action. The therapeutic implications of AMPA receptor potentiators are discussed." [Full Text]

Kessler M, Mutneja MS, Rogers G, Lynch G.
Regional preferences of AMPA receptor modulators determined through agonist binding autoradiography.
Brain Res 1998 Feb 2;783(1):121-6
"Autoradiographic techniques were used to test if positive modulators of AMPA-type glutamate receptors have regionally differentiated effects on ligand binding. Cyclothiazide, a drug with ten fold greater effects on 'flip' than 'flop' splice variants of the receptors, had unequal effects across the subdivisions of hippocampus; i.e., it reduced [3H]AMPA binding in field CA3 with an EC50 of 24 microM and in field CA1 and dentate gyrus with EC50s between 60 and 100 microM. The EC50 for the drug's influence on binding was also significantly lower in the superficial than in the deeper layers of the neocortex, though these differences were not as pronounced as those in the hippocampus. The ampakine CX614, a compound with a modest preference for flop variants, had a slightly lower EC50 for its effects on [3H]AMPA binding in CA1 than in CA3. This result was confirmed with [3H]fluorowillardiine binding. The effects of the ampakine in neocortex tended to be greater in the deeper than superficial layers but this did not reach statistical significance. These results indicate that differential effects of modulators on AMPA receptor subunits are reflected in their relative potency across brain subdivisions. This raises the possibility that subclasses of positive modulators will exhibit a measurable degree of selectivity in their physiological and behavioral influences." [Abstract]

Palmer LC, Hess US, Larson J, Rogers GA, Gall CM, Lynch G.
Comparison of the effects of an ampakine with those of methamphetamine on aggregate neuronal activity in cortex versus striatum.
Brain Res Mol Brain Res 1997 Jun;46(1-2):127-35
"The present study used in situ hybridization to c-fos mRNA to compare the effects of an 'ampakine' (a positive modulator of AMPA type glutamate receptors) with those of methamphetamine on the balance of aggregate neuronal activity in the cortex versus striatum. Methamphetamine (n = 11) induced a marked increase in c-fos mRNA in the dorsomedial quadrant of the striatum and a 21% smaller, but still reliable, increase in the ventrolateral quadrant. The drug also elevated c-fos mRNA levels in the ventral and medial segments of the orbitofrontal cortex but had no detectable effects in motor and somatosensory neocortices. The ampakine (n = 11) caused a near inverse pattern of changes; i.e. a sizable increase in somatosensory labeling and a significant decrease in striatal labeling with statistically insignificant effects in motor and orbitofrontal cortex. Within-rat cortical and striatal values were correlated in both the vehicle (n = 11) and ampakine groups, and appropriate comparisons established that the ampakine caused 27-55% increases in the ratio of cortical to striatal labeling. These results are in accord with the idea that facilitation of glutamatergic transmission has 'network level' effects that are opposite in nature to those resulting from enhanced dopaminergic transmission. The potential relevance of ampakines alone or in conjunction with dopamine antagonists for the treatment of schizophrenia is discussed." [Abstract]

Hess US, Whalen SP, Sandoval LM, Lynch G, Gall CM.
Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion.
Neuroscience. 2003;121(2):509-21.
"It has been proposed that glutamatergic and dopaminergic systems are functionally opposed in their regulation of striatal output. The present study tested the effects of drugs that enhance AMPA-receptor-mediated glutamatergic transmission (ampakines) for their effects on dopamine-related alterations in cortical activity and locomotor behavior. Rats with unilateral 6-hydroxydopamine lesions of the ascending nigro-striatal dopamine system were sensitized to methamphetamine and then tested for methamphetamine-induced circling behavior in the presence and absence of ampakines CX546 and CX614. Both ampakines produced rapid, dose-dependent reductions in circling that were evident within 15 min and sustained through 1 h of behavioral testing. In situ hybridization maps of c-fos mRNA expression showed that in the intact hemisphere, ampakine cotreatment markedly increased c-fos expression in parietal, sensori-motor neocortex above that found in rats treated with methamphetamine alone. Ampakine cotreatment did not augment c-fos expression in frontal, sensori-motor cortex or striatum. Still larger ampakine-elicited effects were obtained in parietal cortex of the dopamine-depleted hemisphere where labeling densities were increased by approximately 60% above values found in methamphetamine-alone rats. With these effects, the hemispheric asymmetry of cortical activation was less pronounced in the ampakine-cotreatment group as compared with the methamphetamine-alone group. These results indicate that positive modulation of AMPA-type glutamate receptors 1) can offset behavioral disturbances arising from sensitized dopamine receptors and 2) increases aggregate neuronal activity in a regionally selective manner that is probably dependent upon behavioral demands." [Abstract]

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Recent Ampakine Research

1) Ren J, Ding X, Greer JJ
J Appl Physiol. 2012 Jul 26;
Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression we hypothesised that ampakines may provide a treatment for other drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline and ampakine CX717, alone and in combination, were measured via i) ventral root recordings from newborn rat brainstem-spinal cord preparations and ii) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg, ip). Pentobarbital induced an approximate 50% reduction in respiratory frequency in vitro (50 ?M) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats, ip).. Severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABAA receptors, that was exacerbated by hypoxic (8% O2) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50-150 ?M) and in vivo (30 mg/kg, ip). While bicuculline caused the significant seizure, CX717 did not. These data demonstrated that ethanol and pentobarbital caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia, hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression. [PubMed Citation] [Order full text from Infotrieve]

2) Silverman JL, Oliver CF, Karras MN, Gastrell PT, Crawley JN
AMPAKINE enhancement of social interaction in the BTBR mouse model of autism.
Neuropharmacology. 2012 Jul 16;
Autism is a neurodevelopmental disorder in which the first diagnostic symptom is unusual reciprocal social interactions. Approximately half of the children diagnosed with an autism spectrum disorder also have intellectual impairments. General cognitive abilities may be fundamental to many aspects of social cognition. Cognitive enhancers could conceivably be of significant benefit to children and adults with autism. AMPAKINE compounds are a novel class of pharmacological agents that act as positive modulators of AMPA receptors to enhance excitatory glutamatergic neurotransmission. This class of compounds was reported to improve learning and memory in several rodent and non-human primate tasks, and to normalize respiratory abnormalities in a mouse model of Rett syndrome. Here we evaluate the actions of AMPA compounds in adult male and female BTBR mice, a well characterized mouse model of autism. Acute treatment with CX1837 and CX1739 reversed the deficit in sociability in BTBR mice on the most sensitive parameter, time spent sniffing a novel mouse as compared to time spent sniffing a novel object. The less sensitive parameter, time in the chamber containing the novel mouse versus time in the chamber containing the novel object, was not rescued by CX1837 or CX1739 treatment. Preliminary data with CX546, in which ?-cyclodextrin was the vehicle, revealed behavioral effects of the acute intraperitoneal and oral administration of vehicle alone. To circumvent the artifacts introduced by the vehicle administration, we employed a novel treatment regimen using pellets of peanut butter for drug delivery. Absence of vehicle treatment effects when CX1837 and CX1739 were given in the peanut butter pellets, to multiple cohorts of BTBR and B6 control mice, confirmed that the pharmacologically-induced improvements in sociability in BTBR were not confounded by the administration procedures. The highest dose of CX1837 improved the cognitive deficit in novel object recognition in BTBR. No drug effects were detected on the high levels of repetitive self-grooming in BTBR. In open field tests, CX1837 and CX1739 did not induce hyperactivity or sedation in either strain. It is interesting to speculate that the ability of CX1837 and CX1739 to restore aspects of sociability in BTBR mice could utilize synaptic mechanisms regulating social cognition, suggesting a potential pharmacological target for interventions to treat symptoms of autism. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

3) Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A
Non-Analgesic Effects of Opioids: Opioid-induced Respiratory Depression.
Curr Pharm Des. 2012 Jun 28;
Opioids induce respiratory depression via activation of µ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone. [PubMed Citation] [Order full text from Infotrieve]

4) Chang PK, Verbich D, McKinney RA
AMPA receptors as drug targets in neurological disease - advantages, caveats, and future outlook.
Eur J Neurosci. 2012 Jun;35(12):1908-16.
Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders. [PubMed Citation] [Order full text from Infotrieve]

5) Baudry M, Kramar E, Xu X, Zadran H, Moreno S, Lynch G, Gall C, Bi X
Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome.
Neurobiol Dis. 2012 Aug;47(2):210-5.
Angelman syndrome (AS) is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene leading to the deletion of E6-associated protein. AS subjects have severe cognitive impairments for which there are no therapeutic interventions. Mouse models (knockouts of the maternal Ube3a gene: 'AS mice') of the disorder have substantial deficits in long-term potentiation (LTP) and learning. Here we report a clinically plausible pharmacological treatment that ameliorates both deficits. AS mice were injected ip twice daily for 5 days with vehicle or the ampakine CX929; drugs of this type enhance fast EPSCs by positively modulating AMPA receptors. Theta burst stimulation (TBS) produced a normal enhancement of field EPSPs in hippocampal slices prepared from vehicle-treated AS mice but LTP decreased steadily to baseline; however, LTP in slices from ampakine-treated AS mice stabilized at levels found in wild-type controls. TBS-induced actin polymerization within dendritic spines, an essential event for stabilizing LTP, was severely impaired in slices from vehicle-treated AS mice but not in those from ampakine-treated AS mice. Long-term memory scores in a fear conditioning paradigm were reduced by 50% in vehicle-treated AS mice but were comparable to values for littermate controls in the ampakine-treated AS mice. We propose that AS is associated with a profound defect in activity-driven spine cytoskeletal reorganization, resulting in a loss of the synaptic plasticity required for the encoding of long-term memory. Notably, the spine abnormality along with the LTP and learning impairments can be reduced by a minimally invasive drug treatment. [PubMed Citation] [Order full text from Infotrieve]

6) Schitine C, Xapelli S, Agasse F, Sardŕ-Arroyo L, Silva AP, De Melo Reis RA, de Mello FG, Malva JO
Ampakine CX546 increases proliferation and neuronal differentiation in subventricular zone stem/progenitor cell cultures.
Eur J Neurosci. 2012 Jun;35(11):1672-83.
Ampakines are chemical compounds known to modulate the properties of ionotropic ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-subtype glutamate receptors. The functional effects attributed to ampakines involve plasticity and the increase in synaptic efficiency of neuronal circuits, a process that may be intimately associated with differentiation of newborn neurons. The subventricular zone (SVZ) is the main neurogenic niche of the brain, containing neural stem cells with brain repair potential. Accordingly, the identification of new pharmaceutical compounds with neurogenesis-enhancing properties is important as a tool to promote neuronal replacement based on the use of SVZ cells. The purpose of the present paper is to examine the possible proneurogenic effects of ampakine CX546 in cell cultures derived from the SVZ of early postnatal mice. We observed that CX546 (50 ?m) treatment triggered an increase in proliferation, evaluated by BrdU incorporation assay, in the neuroblast lineage. Moreover, by using a cell viability assay (TUNEL) we found that, in contrast to AMPA, CX546 did not cause cell death. Also, both AMPA and CX546 stimulated neuronal differentiation as evaluated morphologically through neuronal nuclear protein (NeuN) immunocytochemistry and functionally by single-cell calcium imaging. Accordingly, short exposure to CX546 increased axonogenesis, as determined by the number and length of tau-positive axons co-labelled for the phosphorylated form of SAPK/JNK (P-JNK), and dendritogenesis (MAP2-positive neurites). Altogether, this study shows that ampakine CX546 promotes neurogenesis in SVZ cell cultures and thereby may have potential for future stem cell-based therapies. [PubMed Citation] [Order full text from Infotrieve]

7) de Bartolomeis A, Sarappa C, Magara S, Iasevoli F
Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia.
Eur J Pharmacol. 2012 May 5;682(1-3):1-11.
Antipsychotics are the mainstay of schizophrenia treatment. However, approximately one third of schizophrenic patients do not respond or respond poorly to antipsychotics. Therefore, there is a need for new approaches that can improve schizophrenia treatment significantly. Promising strategies arise from the modulation of glutamatergic system, according to its proposed involvement in schizophrenia pathogenesis. In this review, we critically updated preclinical and clinical data on the modulation of glutamate N-methyl-D-aspartate (NMDA) receptor activity by NMDA-Rs co-agonists, glycine transporters inhibitors, AMPAkines, mGluR5 agonists, NMDA-Rs partial agonists. We focused on: 1) preclinical results in animal models mimicking the pathophysiology of psychosis, mainly believed to be responsible of negative and cognitive symptoms, and predicting antipsychotic-like activity of these compounds; and 2) clinical efficacy in open-label and double-blind trials. Albeit promising preclinical findings for virtually all compounds, clinical efficacy has not been confirmed for D-cycloserine. Contrasting evidence has been reported for glycine and D-serine, that may however have a role as add-on agents. More promising results in humans have been found for glycine transporter inhibitors. AMPAkines appear to be beneficial as pro-cognitive agents, while positive allosteric modulators of mGluR5 have not been tested in humans. Memantine has been proposed in early stages of schizophrenia, as it may counteract the effects of glutamate excitotoxicity correlated to high glutamate levels, slowing the progression of negative symptoms associated to more advanced stages of the illness. [PubMed Citation] [Order full text from Infotrieve]

8) Zheng Y, Balabhadrapatruni S, Masumura C, Darlington CL, Smith PF
Effects of the Putative Cognitive-Enhancing Ampakine, CX717, on Attention and Object Recognition Memory.
Curr Alzheimer Res. 2011 Dec 1;
Ampakines are a class of putative nootropic drug designed to positively modulate the AMPA receptor and have been investigated as a potential treatment for cognitive disorders such as Alzheimer's Disease. Nonetheless, some ampakines such as CX717 have been incompletely characterized in behavioural pharmacological studies. Therefore, in this study, we attempted to further characterize the effects of the ampakine, CX717 (20 mg/kg s.c), on the performance of rats in a 5 choice serial reaction time (5CSRTT) and object recognition memory task, using rats with cognitive deficits caused by bilateral vestibular deafferentation (BVD) as a model. In the 5CSRTT, when the stimulus duration was varied from 5 to 2 sec, the number of incorrect responses was significantly greater for the BVD group compared to sham controls, but significantly less for the CX717 groups, with no significant interaction. With changes in inter-trial interval (ITI), there was a significant effect of surgery/drug and a significant effect of ITI on premature responses, and the BVD group treated with CX717 showed significantly fewer premature responses than the other groups. In the object recognition memory task, CX717 significantly reduced total exploration time and the exploration towards the novel object in both sham and BVD animals. These results suggest that CX717 can reduce the number of incorrect responses in both sham and BVD rats and enhance inhibitory control specifically in BVD rats, in the 5CSRTT. On the other hand, CX717 produced a detrimental effect in the object recognition memory task. [PubMed Citation] [Order full text from Infotrieve]

9) Zheng Y, Balabhadrapatruni S, Masumura C, Darlington CL, Smith PF
Effects of the putative cognitive-enhancing ampakine, CX717, on attention and object recognition memory.
Curr Alzheimer Res. 2011 Dec;8(8):876-82.
Ampakines are a class of putative nootropic drug designed to positively modulate the AMPA receptor and have been investigated as a potential treatment for cognitive disorders such as Alzheimer's Disease. Nonetheless, some ampakines such as CX717 have been incompletely characterized in behavioural pharmacological studies. Therefore, in this study, we attempted to further characterize the effects of the ampakine, CX717 (20 mg/kg s.c), on the performance of rats in a 5 choice serial reaction time (5CSRTT) and object recognition memory task, using rats with cognitive deficits caused by bilateral vestibular deafferentation (BVD) as a model. In the 5CSRTT, when the stimulus duration was varied from 5 to 2 sec, the number of incorrect responses was significantly greater for the BVD group compared to sham controls, but significantly less for the CX717 groups, with no significant interaction. With changes in inter-trial interval (ITI), there was a significant effect of surgery/drug and a significant effect of ITI on premature responses, and the BVD group treated with CX717 showed significantly fewer premature responses than the other groups. In the object recognition memory task, CX717 significantly reduced total exploration time and the exploration towards the novel object in both sham and BVD animals. These results suggest that CX717 can reduce the number of incorrect responses in both sham and BVD rats and enhance inhibitory control specifically in BVD rats, in the 5CSRTT. On the other hand, CX717 produced a detrimental effect in the object recognition memory task. [PubMed Citation] [Order full text from Infotrieve]

10) Sultan P, Gutierrez MC, Carvalho B
Neuraxial morphine and respiratory depression: finding the right balance.
Drugs. 2011 Oct 1;71(14):1807-19.
Morphine is a drug commonly administered via the epidural or intrathecal route, and is regarded by many as the 'gold-standard' single-dose neuraxial opioid due to its postoperative analgesic efficacy and prolonged duration of action. However, respiratory depression is a recognized side effect of neuraxial morphine administered in the perioperative setting. We conducted an extensive review of articles published since 1945 that examine respiratory depression or failure associated with perioperative intrathecal or epidural morphine use. Respiratory depression was previously thought to result from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors. More recently, the preBötzinger complex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preBötzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioid-induced respiratory depression. Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression. There is a wide range of incidences for respiratory depression following neuraxial morphine in a perioperative setting. Disparity of definitions used for the diagnosis of respiratory depression in the literature precludes identification of the exact incidence of this rare event. The optimal neuraxial opioid dose is a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy 'ceiling'. The optimal 'single-shot' intrathecal dose appears to be 0.075-0.15 mg and the ideal 'single-shot' epidural morphine dose is 2.5-3.75 mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. Opioid antagonists such as naloxone to prevent or treat opioid-induced respiratory depression have a number of limitations. Researchers have recently focused on non-opioid drugs such as serotonin receptor agonists. Early evidence suggests that ampakine (?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA]) receptor modulators may be effective at reducing opioid-induced respiratory depression while maintaining analgesia. Sodium/proton exchanger type 3 (NHE3) inhibitors, which act centrally on respiratory pathways, also warrant further study. [PubMed Citation] [Order full text from Infotrieve]

11) Boyle J, Stanley N, James LM, Wright N, Johnsen S, Arbon EL, Dijk DJ
Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep.
J Psychopharmacol. 2012 Aug;26(8):1047-57.
AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100?mg, 300?mg and 1000?mg) and placebo were studied in 16 healthy male volunteers (18-45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000?mg dose. Analysis of the recovery sleep showed that CX717 1000?mg significantly reduced stage 4 and slow-wave sleep (p???0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000?mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep. [PubMed Citation] [Order full text from Infotrieve]

12) Mueller R, Rachwal S, Lee S, Zhong S, Li YX, Haroldsen P, Herbst T, Tanimura S, Varney M, Johnson S, Rogers G, Street LJ
Benzotriazinone and benzopyrimidinone derivatives as potent positive allosteric AMPA receptor modulators.
Bioorg Med Chem Lett. 2011 Oct 15;21(20):6170-5.
AMPA receptors (AMPARs) have been demonstrated to be an important therapeutic CNS target. A series of substituted benzotriazinone and benzopyrimidinone derivatives were prepared with the aim to improve in vivo activity over the previously reported bis-benzoxazinone based AMPAKINE series from our laboratory. These compounds were shown to be potent, positive allosteric AMPAR modulators that have better in vivo activity and improved metabolic stability over the analogous benzoxazinone derivatives. [PubMed Citation] [Order full text from Infotrieve]

13) Power I
An update on analgesics.
Br J Anaesth. 2011 Jul;107(1):19-24.
Recent introduction of new analgesics into the clinic is best described as a slow process with activity classified into two main areas: improving analgesic efficacy/potency and reducing side-effect profile. This review article describes some of the recent advances with an emphasis on use in the acute setting. In this respect, opioids continue to be the mainstay (but not the only) analgesic and there have been important improvements in their clinical effect profile. For example, tapentadol has been introduced as a mixed opioid and norepinephrine uptake inhibitor which, unlike tramadol, does not require metabolic activation and does not suffer from isomer-dependent pharmacodynamics. Opioid antagonists have received much attention recently either used alone, methylnaltrexone (s.c) or alvimopan (p.o), or in combination, Targinact (oxycodone/naloxone), and appear to be effective in reducing opioid side-effects such as those in the gastrointestinal tract. Other agents where there has been recent development include the use of gabapentin, methylxanthines, and local anaesthetics. An interesting area of translation of basic research is in the inhibition of breakdown of endogenous opioids with opiorphin, targeting of the endocannabinoid system, and the use of ampakines to obtund opioid-induced side-effects. It is clear that there is still much work to be done, but the need for highly efficacious analgesics with good side-effect profile remains. [PubMed Citation] [Order full text from Infotrieve]

14) Timm DE, Benveniste M, Weeks AM, Nisenbaum ES, Partin KM
Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation.
Mol Pharmacol. 2011 Aug;80(2):267-80.
At the dimer interface of the extracellular ligand-binding domain of ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH-pyrrolidino(2,1-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bis-alkylsulfonamide (CMPDA) and phenyl-1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously. [PubMed Citation] [Order full text from Infotrieve]

15) Mulzer M, Coates GW
A catalytic route to ampakines and their derivatives.
Org Lett. 2011 Mar 18;13(6):1426-8.
A catalytic domino reaction that efficiently provides access to an important class of heterocycles, the ampakines, is reported. Our approach is based on the cobalt-catalyzed hydroformylation of dihydrooxazines and allows for the facile synthesis of the pharmaceutically interesting compound CX-614 and related substances. [PubMed Citation] [Order full text from Infotrieve]

16) Lynch G, Palmer LC, Gall CM
The likelihood of cognitive enhancement.
Pharmacol Biochem Behav. 2011 Aug;99(2):116-29.
Whether drugs that enhance cognition in healthy individuals will appear in the near future has become a topic of considerable interest. We address this possibility using a three variable system (psychological effect, neurobiological mechanism, and efficiency vs. capabilities) for classifying candidates. Ritalin and modafinil, two currently available compounds, operate on primary psychological states that in turn affect cognitive operations (attention and memory), but there is little evidence that these effects translate into improvements in complex cognitive processing. A second category of potential enhancers includes agents that improve memory encoding, generally without large changes in primary psychological states. Unfortunately, there is little information on how these compounds affect cognitive performance in standard psychological tests. Recent experiments have identified a number of sites at which memory drugs could, in principle, manipulate the cell biological systems underlying the learning-related long-term potentiation (LTP) effect; this may explain the remarkable diversity of memory promoting compounds. Indeed, many of these agents are known to have positive effects on LTP. A possible third category of enhancement drugs directed specifically at integrated cognitive operations is nearly empty. From a neurobiological perspective, two plausible candidate classes have emerged that both target the fast excitatory transmission responsible for communication within cortical networks. One acts on nicotinic receptors (alpha7 and alpha4) that regulate release of the neurotransmitter glutamate while the other ('ampakines') allosterically modulates the glutamate receptors mediating the post-synaptic response (EPSCs). Brain imaging in primates has shown that ampakines expand cortical networks engaged by a complex task; coupled with behavioral data, these findings provide evidence for the possibility of generating new cognitive capabilities. Finally, we suggest that continuing advances in behavioral sciences provide new opportunities for translational work, and that discussions of the social impact of cognitive enhancers have failed to consider the distinction between effects on efficiency vs. new capabilities. [PubMed Citation] [Order full text from Infotrieve]

17) Simmons DA, Mehta RA, Lauterborn JC, Gall CM, Lynch G
Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice.
Neurobiol Dis. 2011 Feb;41(2):436-44.
Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington's disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine, CX929, with a short half-life. Injected once daily for 4-7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in the neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced by 36% the size of intra-nuclear huntingtin aggregates in R6/2 striatum. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases. [PubMed Citation] [Order full text from Infotrieve]

18) Cepeda C, Cummings DM, Hickey MA, Kleiman-Weiner M, Chen JY, Watson JB, Levine MS
Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 Mouse Model of Huntington's Disease: Exercise, Adenosine Receptors and Ampakines.
PLoS Curr. 2010;2
In the R6/2 mouse model of Huntington's disease (HD) we examined the effects of a number of behavioral and pharmacological manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor desensitization, slow deactivation, and facilitate glutamate release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic progression of HD in this model. [PubMed Citation] [Order full text from Infotrieve]

19) Kramár EA, Chen LY, Lauterborn JC, Simmons DA, Gall CM, Lynch G
BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats.
Neurobiol Aging. 2012 Apr;33(4):708-19.
Brain-derived neurotrophic factor (BDNF) has emerged as a possible broad-spectrum treatment for the plasticity losses found in rodent models of human conditions associated with memory and cognitive deficits. We have tested this strategy in the particular case of ovariectomy. The actin polymerization in spines normally found after patterned afferent stimulation was greatly reduced, along with the stabilization of long-term potentiation, in hippocampal slices prepared from middle-aged ovariectomized rats. Both effects were fully restored by a 60-minute infusion of 2 nM BDNF. Comparable rescue results were obtained after elevating endogenous BDNF protein levels in hippocampus with 4 daily injections of a short half-life ampakine (positive modulator of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionate [AMPA]-type glutamate receptors). These results provide the first evidence that minimally invasive, mechanism-based drug treatments can ameliorate defects in spine plasticity caused by depressed estrogen levels. [PubMed Citation] [Order full text from Infotrieve]

20) Kiss T, Hoffmann WE, Hajós M
Delta oscillation and short-term plasticity in the rat medial prefrontal cortex: modelling NMDA hypofunction of schizophrenia.
Int J Neuropsychopharmacol. 2011 Feb;14(1):29-42.
Dysfunction of the prefrontal cortex (PFC) is considered to be an important factor contributing to a decrease in cognitive performance of schizophrenia patients. The medial PFC (mPFC) is innervated by the hippocampus/subiculum, and the subiculum-mPFC pathway is known to be involved in various cognitive processes. Glutamate-containing subicular axons innervate cortical pyramidal neurons and interneurons where AMPA and NMDA receptors are implicated in synaptic transmission. In our experiments, properties of subiculum-mPFC interactions were studied using pathway stimulation and local field potential (LFP) recordings of the mPFC in urethane-anaesthetized rats. Changes in paired-pulse facilitation (PPF) and LFP oscillations, effects of the NMDA receptor antagonist MK-801, and the AMPAkine LY451395 were evaluated. Effects of disruption of the thalamo-cortical loop with local microinjection of lidocaine into the mediodorsal thalamic nucleus (MD) were also studied. Our findings demonstrate that both systemic administration of MK-801 and local MD lidocaine microinjection produce similar changes in LFP oscillations and reduction in PPF. Specifically, it was observed that MK-801 (0.05 mg/kg i.v.) and intra-thalamic lidocaine changed regular, 2 Hz delta oscillation to a less regular 0.5-1.5 Hz delta rhythm. Concurrently, PPF in response to electrical stimulation of the subiculum was significantly attenuated. Administration of the AMPAkine LY451395 (0.01 mg/kg i.v.) reversed the MK-801- and lidocaine-induced changes, and was itself blocked by the AMPA receptor antagonist CP-465022. Analysis of our findings suggests a critical role of cortical interneurons in NMDA/AMPA receptor-mediated changes in thalamo-cortical oscillations and PPF, and contributes to our understanding of the NMDA hypofunction model of schizophrenia. [PubMed Citation] [Order full text from Infotrieve]