5-HT6 Receptor Research -- Neurotransmitter.net

(Updated 3rd or 4th quarter 2002)

Svenningsson P, Tzavara ET, Liu F, Fienberg AA, Nomikos GG, Greengard P.
DARPP-32 mediates serotonergic neurotransmission in the forebrain.
Proc Natl Acad Sci U S A 2002 Mar 5;99(5):3188-93
"Here we report that serotonin regulates DARPP-32 phosphorylation both in vitro and in vivo. Stimulation of 5-hydroxy-tryptamine (5-HT4 and 5-HT6) receptors causes an increased phosphorylation state at Thr34–DARPP-32, the protein kinase A site, and a decreased phosphorylation state at Thr75–DARPP-32, the cyclin-dependent kinase 5 site. Furthermore, stimulation of 5-HT2 receptors increases the phosphorylation state of Ser137–DARPP-32, the casein kinase-1 site. Behavioral and gene transcriptional effects induced by compounds that selectively release serotonin were greatly reduced in DARPP-32 knockout mice." [Full Text]
Boess, Frank G., Riemer, Claus, Bos, Michael, Bentley, Jane, Bourson, Anne, Sleight, Andrew J.
The 5-Hydroxytryptamine6 Receptor-Selective radioligand [3H]Ro 63-0563 Labels 5-Hydroxytryptamine Receptor Binding Sites in Rat and Porcine Striatum
Mol Pharmacol 1998 54: 577-583 [Full Text]

Miguel-Hidalgo JJ.
SB-271046 (SmithKline Beecham).
Curr Opin Investig Drugs 2001 Jan;2(1):118-22
"Data recently presented at the Society for Neuroscience annual meeting in November 2000 demonstrated that administration of SB-271046 resulted in a signficant increase in glutamate and aspartate levels in the frontal cortex, without affecting noradrenaline, dopamine or 5-HT levels. This was stated to suggest that 5-HT6 antagonists might therefore be useful for treating cognitive dysfunction [390469]." [Abstract]
Woolley ML, Bentley JC, Sleight AJ, Marsden CA, Fone KC.
A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze.
Neuropharmacology 2001 Aug;41(2):210-9
"This study investigates the effect of intracerebroventricular administration of a 5-ht6 antisense oligonucleotide (AO) complementary to bases 1-18 of the rat 5-ht6 cDNA initiation sequence (Mol. Pharmacol. 43 (1993) 320) (1.5 microg twice daily for six days) and i.p. injection of a selective 5-ht6 receptor antagonist Ro 04-6790 (10 or 30 mg/kg once daily for three days) on acquisition and retention in the Morris water maze. Neither the 5-ht6 AO (which reduced cortical [3H]-LSD binding sites by 10-16%) nor Ro 04-6790 affected acquisition, but both enhanced retention of the learned platform position such that rats spent significantly longer searching the trained platform position than any other area during the probe tests. Furthermore, neither AO nor Ro 04-6790 had any effect on the time taken to reach a raised visible platform, indicating that visual acuity was unimpaired. In addition, AO reduced both food consumption and body weight and the later effect was also seen following Ro 04-6790, suggesting a role for the 5-ht6 receptor in the regulation of feeding. Hence, while the underlying mechanism remains unclear, enhanced retention of spatial learning following both AO and 5-ht6 antagonist administration strongly indicate a role for this receptor in memory processes." [Abstract]

Stefulj J, Jernej B, Cicin-Sain L, Rinner I, Schauenstein K.
mRNA expression of serotonin receptors in cells of the immune tissues of the rat.
Brain Behav Immun 2000 Sep;14(3):219-24
"All 13 rat 5-HT receptor genes cloned so far were examined in ex vivo isolated spleen, thymus, and peripheral blood lymphocytes, as well as in mitogen-stimulated spleen cells. Positive signals were obtained for 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7 receptor mRNAs in all three compartments. Mitogen (ConA and PWM) stimulated cells additionally expressed mRNA corresponding to the 5HT-3 receptor subtype. In contrast, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT4, 5-HT5A, and 5-HT5B mRNAs were not detected in any of the examined cell populations." [Abstract]

Branchek, Theresa A., Blackburn, Thomas P.
5-ht6 Receptors as Emerging Targets for Drug Discovery
Annu. Rev. Pharmacol. Toxicol. 2000 40: 319-334
"Surprisingly, 5-ht6 receptors appear to regulate cholinergic neurotransmission in the brain, rather than the expected interaction as modulators of dopaminergic transmission. This interaction predicts a possible role for 5-ht6 receptor antagonists in the treatment of learning and memory disorders." [Abstract]

Tsai SJ, Liu HC, Liu TY, Wang YC, Hong CJ.
Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease.
Neurosci Lett 1999 Dec 3;276(2):138-9
"Statistical analysis showed a significant difference in the genotype and gene frequencies between the AD group and the normal controls (P = 0.006; and P = 0.023, respectively). These findings indicate that the 267C allele of the 5-HT6 gene is a risk factor for AD." [Abstract]

Hamon M, Doucet E, Lefevre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Verge D.
Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors.
Neuropsychopharmacology 1999 Aug;21(2 Suppl):68S-76S
"Studies using polyclonal anti-5-HT6 receptor antibodies and an antisense oligonucleotide were performed in order to investigate further the function(s) of 5-HT6 receptors in the rat brain. Immunocytochemistry at the light and electron microscope levels showed that 5-HT6 receptors are mainly confined to the dendritic compartment, suggesting that they could mediate 5-HT actions on neuronal firing. In some limbic areas, 5-HT6 receptor-like immunoreactivity is also associated with neuronal cilia with yet unknown functions. Continuous i.c.v. infusion with an antisense oligonucleotide for 3-4 days resulted in decreased 5-HT6 receptor-like immunostaining of the nucleus accumbens and anxiogenic behaviours in the social interaction and elevated plus maze tests." [Abstract]

Routledge, Carol, Bromidge, Steven M., Moss, Stephen F., Price, Gary W., Hirst, Warren, Newman, Helen, Riley, Graham, Gager, Tracey, Stean, Tania, Upton, Neil, Clarke, Stephen E., Brown, Anthony M., Middlemiss, Derek N.
Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist
Br. J. Pharmacol. 2000 130: 1606-1612
"SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of 0.1 mg kg-1 p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 µM) and brain concentrations of 0.01 – 0.04 µM at Cmax.

These data, together with the observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (10 mg kg-1, 2 – 6 h pre-test) and Ro 04-6790 (1 – 30 mg kg-1, 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT6 receptors." [Abstract]

Boess FG, Monsma FJ Jr, Sleight AJ.
Identification of residues in transmembrane regions III and VI that contribute to the ligand binding site of the serotonin 5-HT6 receptor.
J Neurochem 1998 Nov;71(5):2169-77
"We have examined the ligand binding site of the serotonin 5-HT6 receptor using site-directed mutagenesis. Replacing the highly conserved Asp106 in transmembrane region III by asparagine eliminated D-[3H]-lysergic acid diethylamide ([3H]LSD) binding to the mutant receptor transiently expressed in HEK293 cells. The potency of 5-HT and LSD to stimulate adenylyl cyclase was reduced by 3,600- and 500-fold, respectively, suggesting that an ionic interaction between the positively charged amino group of 5-HT and D106 is essential for high-affinity binding and important for receptor activation. In addition, basal cyclic AMP levels in cells expressing this mutant were increased. Mutation of a tryptophan residue one helix turn toward the extracellular side of transmembrane region III (Trp102) to phenylalanine produced significant changes in the binding affinity and potency of several ligands, consistent with a role of this residue in the formation of the ligand binding site. The exchange of two neighboring residues in the carboxy-terminal half of transmembrane region VI (Ala287 and Asn288) for leucine and serine resulted in a mutant receptor with increased affinities (seven- to 30-fold) for sumatriptan and several ergopeptine ligands. The identification of these interactions will help to improve models of the 5-HT6 receptor ligand binding site." [Abstract]
Boess, Frank G., Monsma, Frederick J., Jr., Meyer, Valerie, Zwingelstein, Catherine, Sleight, Andrew J.
Interaction of Tryptamine and Ergoline Compounds with Threonine 196 in the Ligand Binding Site of the 5-Hydroxytryptamine6 Receptor
Mol Pharmacol 1997 52: 515-523
"The combination of site-directed mutagenesis (guided by knowledge obtained for related receptors) with a series of related ligands differing in a particular structural feature has allowed the identification of a specific interaction between Thr196 in transmembrane region V of the 5-HT6 receptor and the indole nitrogen of N1-unsubstituted ergolines and tryptamines." [Full Text]

Sleight AJ, Monsma FJ Jr, Borroni E, Austin RH, Bourson A.
Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides.
Behav Brain Res 1996;73(1-2):245-8
"Rats were treated with either saline, antisense (AO) or scrambled oligonucleotides (SO) for 4 days. Treatment with AO reduced the number of [3H]LSD binding sites in the frontal lobes by 30% but had no significant effect on the number of 5-HT1A and 5-HT2A receptor binding sites in the cortex of the rats. A behavioural syndrome of yawning, stretching and chewing, however, was observed in AO treated rats but not in any of the other treatment groups. This AO-specific behaviour had returned to normal 5 days after cessation of the oligodeoxynucleotide treatment." [Abstract]
Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW.
Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.
J Neurochem 1996 Jan;66(1):47-56
"The human 5-HT6 amino acid sequence is 89% similar to the corrected rat sequence. The recombinant human 5-HT6 receptor is positively coupled to adenylyl cyclase and has pharmacological properties similar to the rat receptor with high affinity for several typical and atypical antipsychotics, including clozapine. The receptor is expressed in several human brain regions, most prominently in the caudate nucleus. The gene for the receptor maps to the human chromosome region 1p35-p36. This localization overlaps that established for the serotonin 5-HT1D alpha receptor, suggesting that these may be closely linked." [Abstract]

Dawson LA, Nguyen HQ, Li P.
The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus.
Neuropsychopharmacology 2001 Nov;25(5):662-8
"Preclinical evidence has suggested a possible role for the 5-HT(6) receptor in the treatment of cognitive dysfunction. However, currently there is little neurochemical evidence suggesting the mechanism(s) which may be involved. Using the selective 5-HT(6) antagonist SB-271046 and in vivo microdialysis, we have evaluated the effects of this compound on the modulation of basal neurotransmitter release within multiple brain regions of the freely moving rat. SB-271046 produced no change in basal levels of dopamine (DA), norepinephrine (NE) or 5-HT in the striatum, frontal cortex, dorsal hippocampus or nucleus accumbens. Similarly, this compound had no effect on excitatory neurotransmission in the striatum or nucleus accumbens. Conversely, SB-271046 produced 3- and 2-fold increases in extracellular glutamate levels in both frontal cortex and dorsal hippocampus, respectively. These effects were completely attenuated by infusion of tetrodotoxin but unaffected by the muscarinic antagonist, atropine. Here we demonstrate for the first time the selective enhancement of excitatory neurotransmission by SB-271046 in those brain regions implicated in cognitive and memory function, and provide mechanistic evidence in support of a possible therapeutic role for 5-HT(6) receptor antagonists in the treatment of cognitive and memory dysfunction." [Abstract]

Gerard C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L, Doucet E, Hamon M, el Mestikawy S.
Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system.
Brain Res 1997 Jan 23;746(1-2):207-19
"Immunoautoradiographic experiments with antibodies affinity-purified on Affi-Gel coupled to the peptide antigen showed that 5-HT6-like immunoreactive material was abundant in the olfactory tubercle (plexiform layer), cerebral cortex (frontal and entorhinal areas), nucleus accumbens, striatum, hippocampus (strata oriens and radiatum of the CA1 area, molecular layer of the dentate gyrus) and the molecular layer of the cerebellum. A specific immunolabeling, but at moderate intensity, was also observed in the thalamus, substantia nigra, superficial layer of the superior colliculus, motor trigeminal nucleus and facial nucleus. In contrast, no 5-HT6-like immunoreactive material was found in white matter areas. As the regional distribution of 5-HT6 receptor-like immunoreactivity matched generally that previously found for the 5-HT6 receptor mRNA, one could infer that this receptor protein is addressed in the vicinity of its synthesis site, i.e. on somas and/or dendrites. Indeed, immunohistochemistry at the light and electron microscope level showed that 5-HT6-like immunoreactivity was associated with dendritic processes in both the striatum and the dentate gyrus of the hippocampus. The relative abundance of 5-HT6 receptor-like immunoreactivity in extrapyramidal and limbic areas suggests that 5-HT6 receptors may participate in the serotoninergic control of motor function and mood-dependent behavior, respectively." [Abstract]

Lauren P. Baker, Mark D. Nielsen, Soren Impey, Mark A. Metcalf, Steven W. Poser, Guy Chan, Karl Obrietan, Mark W. Hamblin, and Daniel R. Storm
Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7A Receptor
J. Biol. Chem. 273: 17469-17476, July 1998.
"In summary, these data demonstrate that 5-HT6 acts as a typical Gs-coupled receptor by stimulating AC5, but not AC1 or AC8. The discovery that 5-HT7A stimulates AC1 and AC8 through increases in intracellular Ca2+ provides a novel mechanism for serotonergic regulation of intracellular cAMP in the brain and other tissues." [Full Text]

East SZ, Burnet PW, Leslie RA, Roberts JC, Harrison PJ.
5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: Autoradiographic studies with [125I]SB-258585.
Synapse 2002 Sep;45(3):191-9
"In summary, [(125)I]SB-258585 is a suitable radioligand for studies of human brain 5-HT(6)R binding sites and shows that their distribution is broadly similar to that of the rodent. The lack of effect of schizophrenia or antipsychotic drug administration on [(125)I]SB-258585 binding suggests that an altered receptor density does not contribute to any involvement which the 5-HT(6)R may have in the disease or its treatment." [Abstract]

Masellis M, Basile VS, Meltzer HY, Lieberman JA, Sevy S, Goldman DA, Hamblin MW, Macciardi FM, Kennedy JL.
Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.
Schizophr Res 2001 Jan 15;47(1):49-58 [Abstract]

Ohmori O, Shinkai T, Hori H, Nakamura J.
Novel polymorphism in the 5'-upstream region of the human 5-HT6 receptor gene and schizophrenia.
Neurosci Lett 2001 Sep 7;310(1):17-20
"Our results suggest that the 5-HT6 receptor gene polymorphism does not confer increased susceptibility to schizophrenia."
[Abstract]

Shinkai T, Ohmori O, Kojima H, Terao T, Suzuki T, Abe K.
Association study of the 5-HT6 receptor gene in schizophrenia.
Am J Med Genet 1999 Apr 16;88(2):120-2
"No significant positive association between the 5-HT6 receptor genotype and schizophrenia was observed. Our results suggests that the 267C/T polymorphism of the 5-HT6 receptor gene may not be involved in the susceptibility to schizophrenia." [Abstract]

Rogers DC, Hagan JJ.
5-HT6 receptor antagonists enhance retention of a water maze task in the rat.
Psychopharmacology (Berl) 2001 Nov;158(2):114-9
" In the water maze, administration of SB-271046-A or SB-357134-A (3 or 10 mg/kg) had no effect on learning per se. At 10 mg/kg, however, both compounds produced a significant improvement in retention of a previously learned platform position when tested 7 days after training. By contrast, the acetylcholinesterase inhibitor, Aricept (donepezil, 0.1, 0.3 mg/kg PO) had no effect in this task."
[Abstract]

Kohen R, Fashingbauer LA, Heidmann DE, Guthrie CR, Hamblin MW.
Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop.
Brain Res Mol Brain Res 2001 Jun 20;90(2):110-7
"These data suggest that constitutive activity may be important to 5-HT6 receptor activity in vivo and that, unlike some other G-protein coupled receptors, alteration in the BBXXB CIII-loop motif reduces rather than further activates basal activity of the murine 5-HT6 receptor." [Abstract]

Matsumoto M, Yoshioka M.
[Possible involvement of serotonin receptors in anxiety disorders]
Nippon Yakurigaku Zasshi 2000 Jan;115(1):39-44
"Inactivation of mRNA encoding 5-HT6 receptors using antisense oligonucleotide produced decreases in cortical 5-HT release enhanced by anxiety. These observations lead to the suggestion that different mechanisms, mediated by various 5-HT receptors, are involved in the pathogenesis of anxiety." [Abstract]

Healy DJ, Meador-Woodruff JH.
Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain.
Neuropsychopharmacology 1999 Sep;21(3):341-51
"MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and glutamatergic systems."
[Abstract]

Pena-Rangel MT, Mercado R, Hernandez-Rodriguez J.
Regulation of glial Na+/K+-ATPase by serotonin: identification of participating receptors.
Neurochem Res 1999 May;24(5):643-9
"Altogether, these results show that serotonin modulates glial Na+/K+-ATPase activity in the brain, apparently not through only one type of 5-HT receptor. It seems that the receptor system involved is different according to the brain region. In cerebral cortex, the response seems to be mediated by 5-HT1A as well as in hippocampus but not in cerebellum where 5-HT6 appears as the receptor system involved." [Abstract]

Bentley, Jane C., Bourson, Anne, Boess, Frank G., Fone, Kevin C.F., Marsden, Charles A., Petit, Nadine, Sleight, Andrew J.
Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats
Br. J. Pharmacol. 1999 126: 1537-1542
"These data suggest that systemic injection of the 5-HT6 antagonist, Ro 04-6790, produces a stretching behaviour that appears to be mediated by an increase in cholinergic neurotransmission in the CNS and which could be a useful functional correlate for 5-HT6 receptor blockade. There is no evidence for dopamine D2-like receptor involvement in this behaviour." [Abstract]

Bourson, A, Boess, FG, Bos, M, Sleight, AJ
Involvement of 5-HT6 receptors in nigro-striatal function in rodents
Br. J. Pharmacol. 1998 125: 1562-1566
"Ro 04-6790 (3, 10 and 30 mg kg(-1) i.p.) did not itself induce rotational behaviour in rats with unilateral 6- hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle nor did it affect the rotational behaviour induced by either L-Dopa or amphetamine. 5-HT6 receptor antagonism inhibited the rotational behaviour of 6-OHDA lesioned rats induced by treatment with the muscarinic antagonists scopolamine and atropine. The data support earlier conclusions from experiments with antisense oligonucleotides that the 5-HT6 receptor is involved in the control of acetylcholine neurotransmission in the rat brain." [Abstract]

Hirst, Warren D., Minton, Jayne A.L., Bromidge, Steven M., Moss, Stephen F., Latter, Alison J., Riley, Graham, Routledge, Carol, Middlemiss, Derek N., Price, Gary W.
Characterization of [125I]-SB-258585 binding to human recombinant and native 5-HT6 receptors in rat, pig and human brain tissue
Br. J. Pharmacol. 2000 130: 1597-1605
"The pKi rank order of potency for a number of compounds, determined in competition binding assays with [125I]-SB-258585, at human caudate putamen membranes was: SB-271046>SB-258585>SB-214111>methiothepin>clozapine>5-Me-OT>5-HT>Ro 04-6790>mianserin>ritanserin=amitriptyline>5-CT>mesulergine. Similar profiles were obtained from pig and rat striatal membranes and recombinant 5-HT6 receptors; data from the latter correlated well with [3H]-LSD binding." [Abstract]

Purohit A, Herrick-Davis K, Teitler M.
Creation, expression, and characterization of a constitutively active mutant of the human serotonin 5-HT6 receptor.
Synapse 2003 Mar;47(3):218-24
"The serotonin 5-HT(6) receptor, a G-protein-coupled receptor, displays high affinity for antipsychotic, antidepressant, and psychotropic drugs. We created a constitutively active form of the human 5-HT(6) receptor in order to probe the molecular domains of receptor activation and to determine if inverse agonist activities of antipsychotic drugs contribute to their clinical profile. Previous studies from our laboratory support a critical role for the c-terminal region of the third intracellular loop (il3) in the activation of G(q)-coupled serotonin receptors. In the present study, PCR-based mutagenesis was used to mutate serine 267 (S6.34) in the c-terminal region of il3 to lysine (S267K). The native and S267K 5-HT(6) receptors were expressed in COS-7 cells to study the functional effects of the mutation. The S267K receptor shows 10-fold higher affinity for serotonin than the native receptor and demonstrates agonist-independent activity. Clozapine decreased the basal activity of the S267K receptor to vector control levels. Therefore, we can conclude that the S267K mutation renders the 5-HT(6) receptor constitutively active and that clozapine is an inverse agonist at the mutant 5-HT(6) receptor. These results indicate that the c-terminal region of il3 of the G(s)-coupled 5-HT(6) receptor is a key domain for G-protein coupling, similar to the G(q)-coupled 5-HT receptors. The inverse agonist action of clozapine indicates that drugs displaying competitive antagonist activity at native 5-HT(6) receptors may display inverse agonist activity at the constitutively activated form of the receptor." [Abstract]

Olsen MA, Nawoschik SP, Schurman BR, Schmitt HL, Burno M, Smith DL, Schechter LE.
Identification of a human 5-HT6 receptor variant produced by alternative splicing.
Brain Res Mol Brain Res 1999 Feb 5;64(2):255-63
"The splicing pattern seen for this transcript was not detected in rat or mouse whole brain cDNA by PCR due to the lack of a consensus 5' donor site. Coexpression of the variant 5-HT6 transcript and the full length 5-HT6 transcript was observed in caudate and substantia nigra but not in hippocampus, cortex, cerebellum and thalamus. Transient transfection of a 5-HT6 variant construct into Cos-7 cells demonstrated that a truncated receptor was translocated to the membrane but appeared nonfunctional." [Abstract]

Yau JL, Noble J, Widdowson J, Seckl JR.
Impact of adrenalectomy on 5-HT6 and 5-HT7 receptor gene expression in the rat hippocampus.
Brain Res Mol Brain Res 1997 Apr;45(1):182-6
"Here, we show that pharmacological adrenalectomy increases 5-HT6 and 5-HT7 receptor mRNA expression in specific hippocampal subfields, effects partly reversed by corticosterone replacement." [Abstract]

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Recent 5-HT6 Receptor Research
1) Wu J, Li Q, Bezprozvanny I
Evaluation of Dimebon in cellular model of Huntington's disease.
Mol Neurodegener. 2008;3:15.
ABSTRACT: BACKGROUND: Dimebon is an antihistamine compound with a long history of clinical use in Russia. Recently, Dimebon has been proposed to be useful for treating neurodegenerative disorders. It has demonstrated efficacy in phase II Alzheimer's disease (AD) and Huntington's disease (HD) clinical trials. The mechanisms responsible for the beneficial actions of Dimebon in AD and HD remain unclear. It has been suggested that Dimebon may act by blocking NMDA receptors or voltage-gated Ca2+ channels and by preventing mitochondrial permeability pore transition. RESULTS: We evaluated the effects of Dimebon in experiments with primary striatal neuronal cultures (MSN) from wild type (WT) mice and YAC128 HD transgenic mice. We found that Dimebon acts as an inhibitor of NMDA receptors (IC50 = 10 muM) and voltage-gated calcium channels (IC50 = 50 muM) in WT and YAC128 MSN. We further found that application of 50 muM Dimebon stabilized glutamate-induced Ca2+ signals in YAC128 MSN and protected cultured YAC128 MSN from glutamate-induced apoptosis. Lower concentrations of Dimebon (5 muM and 10 muM) did not stabilize glutamate-induced Ca2+ signals and did not exert neuroprotective effects in experiments with YAC128 MSN. Evaluation of Dimebon against a set of biochemical targets indicated that Dimebon inhibits alpha-Adrenergic receptors (alpha1A, alpha1B, alpha1D, and alpha2A), Histamine H1 and H2 receptors and Serotonin 5-HT2c, 5-HT5A, 5-HT6 receptors with high affinity. Dimebon also had significant effect on a number of additional receptors. CONCLUSION: Our results suggest that Ca2+ and mitochondria stabilizing effects may, in part, be responsible for beneficial clinical effects of Dimebon. However, the high concentrations of Dimebon required to achieve Ca2+ stabilizing and neuroprotective effects in our in vitro studies (50 muM) indicate that properties of Dimebon as cognitive enhancer are most likely due to potent inhibition of H1 histamine receptors. It is also possible that Dimebon acts on novel high affinity targets not present in cultured MSN preparation. Unbiased evaluation of Dimebon against a set of biochemical targets indicated that Dimebon efficiently inhibited a number of additional receptors. Potential interactions with these receptors need to be considered in interpretation of results obtained with Dimebon in clinical trials. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

2) Alcalde E, Mesquida N, Frigola J, L�pez-P�rez S, Merc� R
Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6 receptor ligands.
Org Biomol Chem. 2008 Oct 21;6(20):3795-810.
A series of novel indene derivatives designed by a scaffold selection gave access to several examples of (Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT(6) receptor ligands. Different synthetic multistep routes could be applied to these target compounds, each with their own complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence employing a modified Horner-Wadsworth-Emmons reaction, but better results were obtained with a procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed immediately by dehydration with acid and hydrolysis/isomerization under basic catalysis. (3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively reduced to indenylsulfonamides using an optimized procedure with AlH(3)-NMe(2)Et. The binding at the 5-HT(6) receptor was with moderate affinity (K(i) = 216.5 nM) for the (Z)-benzylideneindenylsulfonamide and enhanced affinity for the simple indenylsulfonamide counterpart (K(i) = 50.6 nM). Selected indenylsulfonamides were then tested, showing K(i) values as low as 20.2 nM. [PubMed Citation] [Order full text from Infotrieve]

3) Trani G, Baddeley SM, Briggs MA, Chuang TT, Deeks NJ, Johnson CN, Khazragi AA, Mead TL, Medhurst AD, Milner PH, Quinn LP, Ray AM, Rivers DA, Stean TO, Stemp G, Trail BK, Witty DR
Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists.
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5698-700.
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios. [PubMed Citation] [Order full text from Infotrieve]

4) Johnson CN, Ahmed M, Miller ND
5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia.
Curr Opin Drug Discov Devel. 2008 Sep;11(5):642-54.
Several serious neurological and psychiatric disorders are associated with cognitive impairment. Thus, drugs targeting the cognitive symptoms of these diseases would be expected to provide significant benefits to these patient populations. A growing body of preclinical evidence has supported the use of serotonin 5-HT6 receptor antagonism as a promising mechanism for treating cognitive dysfunction. Following the discovery of a new generation of 5-HT6 receptor ligands with improved physicochemical properties, leading to superior brain penetration, additional support for the 5-HT6 hypothesis has been provided by clinical trial data for three molecules in drug development. [PubMed Citation] [Order full text from Infotrieve]

5) Tarazi FI, Moran-Gates T, Wong EH, Henry B, Shahid M
Asenapine induces differential regional effects on serotonin receptor subtypes.
J Psychopharmacol. 2008 Aug 21;
Abstract Asenapine, a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has high affinity for a wide range of receptors, including the serotonergic receptors 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7. We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT1A, 5-HT2A and 5-HT2C. Rats were given asenapine (0.03, 0.1 or 0.3 mg/kg) subcutaneously twice daily or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), caudate putamen, nucleus accumbens, hippocampal CA1 and CA3 regions, and entorhinal cortex and processed for in-vitro receptor autoradiography. Asenapine 0.1 and 0.3 mg/kg significantly increased 5-HT1A binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal CA1 region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/kg) significantly decreased 5-HT2A binding by a similar degree in mPFC (40%, 44%, 47%, respectively) and DFC (45%, 51%, 52%) (all P < 0.05), but did not alter 5-HT2A binding in the other brain regions studied. In contrast to the effects on 5-HT1A and 5-HT2A receptors, asenapine did not alter 5-HT2C binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT1A and 5-HT2A receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine. [PubMed Citation] [Order full text from Infotrieve]

6) Geldenhuys WJ, Van der Schyf CJ
Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease.
Curr Top Med Chem. 2008;8(12):1035-48.
Recently, the serotonin 5-HT(6) receptor has been identified as a drug target for attenuating cognitive deficits associated with Alzheimer's disease (AD). Additionally, this receptor may also play a role in schizophrenia, anxiety and obesity. Reports in the literature suggest that the production of selective antagonists for the 5-HT(6) receptor has increased during the last 10 years, with some compounds currently in clinical trials for the treatment of AD. In this review, we will address the rationale for using 5-HT(6) receptor antagonists in AD, as well as report on current advances in the understanding of the structure-activity relationships required to synthesize 5-HT(6) receptor antagonists. [PubMed Citation] [Order full text from Infotrieve]

7) Dolevicz�nyi Z, Vizi ES, Gacs�lyi I, Pallagi K, Volk B, H�rsing LG, Halmos G, Lendvai B, Zelles T
5-HT6/7 receptor antagonists facilitate dopamine release in the cochlea via a GABAergic disinhibitory mechanism.
Neurochem Res. 2008 Nov;33(11):2364-72.
In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume superfusion techniques we tested 5-HT(6) and 5-HT(7) receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic conditions using currently available and new 5-HT(6) and 5-HT(7) antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT(7) antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT(6) receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type of receptor. Moreover, the mixed 5-HT(6/7) antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement of an indirect neural mechanism through an inhibitory system. In the presence of the GABA(A) receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic inhibitory tone on dopaminergic nerve endings. The mixed 5-HT(7)/D(4) receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals in the cochlea may have a role in the treatment of sensorineural hearing loss. [PubMed Citation] [Order full text from Infotrieve]

8) Riccio O, Potter G, Walzer C, Vallet P, Szab� G, Vutskits L, Kiss JZ, Dayer AG
Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6.
Mol Psychiatry. 2008 Jul 29;
The discovery that a common polymorphism (5-HTTLPR, short variant) in the human serotonin transporter gene (SLC6A4) can influence personality traits and increase the risk for depression in adulthood has led to the hypothesis that a relative increase in the extracellular levels of serotonin (5-HT) during development could be critical for the establishment of brain circuits. Consistent with this idea, a large body of data demonstrate that 5-HT is a strong neurodevelopmental signal that can modulate a wide variety of cellular processes. In humans, serotonergic fibers appear in the developing cortex as early as the 10th gestational week, a period of intense neuronal migration. In this study we hypothesized that an excess of 5-HT could affect embryonic cortical interneuron migration. Using time-lapse videometry to monitor the migration of interneurons in embryonic mouse cortical slices, we discovered that the application of 5-HT decreased interneuron migration in a reversible and dose-dependent manner. We next found that 5-HT6 receptors were expressed in cortical interneurons and that 5-HT6 receptor activation decreased interneuron migration, whereas 5-HT6 receptor blockade prevented the migratory effects induced by 5-HT. Finally, we observed that interneurons were abnormally distributed in the cerebral cortex of serotonin transporter gene (Slc6a4) knockout mice that have high levels of extracellular 5-HT. These results shed new light on the neurodevelopmental alterations caused by an excess of 5-HT during the embryonic period and contribute to a better understanding of the cellular processes that could be modulated by genetically controlled differences in human 5-HT homeostasis.Molecular Psychiatry advance online publication, 29 July 2008; doi:10.1038/mp.2008.89. [PubMed Citation] [Order full text from Infotrieve]

9) Upton N, Chuang TT, Hunter AJ, Virley DJ
5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease.
Neurotherapeutics. 2008 Jul;5(3):458-69.
Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach. [PubMed Citation] [Order full text from Infotrieve]

10) Marcos B, Chuang TT, Gil-Bea FJ, Ramirez MJ
Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat.
Br J Pharmacol. 2008 Oct;155(3):434-40.
BACKGROUND AND PURPOSE: The beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits. EXPERIMENTAL APPROACH: The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046. KEY RESULTS: Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

11) Da Silva Costa V, Duchatelle P, Boulouard M, Dauphin F
Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse.
Neuropsychopharmacology. 2008 Jul 2;
Studies have recently suggested that blockade of 5-HT6 receptors (5-HT6R) improves memory processes. As episodic memory alteration is one of the first deficits observed during normal aging and in neurological and neuropsychiatric disorders (Alzheimer's disease, schizophrenia), the present study sought to characterize the effects of 5-HT6R blockade on spatial recognition memory, which can be considered as 'episodic-like' memory, in rodents. We quantified the effects of the selective 5-HT6R antagonist SB-271046 (10 mg/kg, i.p.), using the two-trial place recognition task in the Y-maze, on acquisition, consolidation, and retrieval of spatial recognition memory in young adult mice (6-week-old; intertrial intervals (ITIs) 30, 60, 120, 240, and 360 min) and on the consolidation of spatial recognition memory in aged mice (3-, 12-, 18-, and 21-month-old; ITI 60 and 240 min). SB-271046-treated young adult mice explored the new arm more after a 240-min (pre-acquisition) and 360-min (post-acquisition) ITI, whereas vehicle-treated animals failed to discriminate the new arm when the ITI exceeded 120 min (pre-acquisition) or 240 min (post-acquisition). Aged mice, which expressed spatial memory deficits, explored the new arm more after a 60-min ITI (21-month-old) and a 240-min ITI (18- and 21-month-old) when treated with SB-271046. Consequently, 5-HT6R blockade improves spatial recognition memory in adult mice and reverses age-related consolidation deficits of episodic-like memory. This study provides further support for the use of 5-HT6R antagonists in the treatment of episodic memory disorders related to aging as well as neurological disorders such as Alzheimer's disease and schizophrenia.Neuropsychopharmacology advance online publication, 2 July 2008; doi:10.1038/npp.2008.94. [PubMed Citation] [Order full text from Infotrieve]

12) Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ
A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands.
Bioorg Med Chem Lett. 2008 Jul 15;18(14):3929-31.
A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported. [PubMed Citation] [Order full text from Infotrieve]

13) Kambhampati R, Konda J, Reballi V, Shinde AK, Dubey PK, Nirogi RV
Design, synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT(6) receptor ligands.
J Enzyme Inhib Med Chem. 2008 Jun;23(3):302-12.
The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT6 receptors. [PubMed Citation] [Order full text from Infotrieve]

14) Dupuis DS, Mannoury la Cour C, Chaput C, Verri�le L, Lavielle G, Millan MJ
Actions of novel agonists, antagonists and antipsychotic agents at recombinant rat 5-HT6 receptors: a comparative study of coupling to G alpha s.
Eur J Pharmacol. 2008 Jul 7;588(2-3):170-7.
Though 5-HT6 receptors are targets for the treatment of schizophrenia and other psychiatric disorders, the influence of drugs upon signal transduction has not been extensively characterized. Herein, we employed a Scintillation Proximity Assay (SPA)/antibody-immunocapture procedure of coupling to G alpha s to evaluate the interaction of a broad range of novel agonists, antagonists and antipsychotics at rat 5-HT(6) receptors stably expressed in HEK293 cells. Serotonin (pEC(50), 7.7) increased [35S]GTP gamma S binding to G alpha s by ca 2-fold without affecting binding to Gi/o or Gq. LSD (9.2), 5-MeODMT (7.9), 5-CT (7.0) and tryptamine (6.1) were likewise full agonists. In contrast, the novel sulfonyl derivatives, WAY181,187 (9.1) and WAY208,466 (7.8), behaved as partial agonists and attenuated the actions of 5-HT. SB271,046 and SB258,585 abolished activation of G alpha s by 5-HT with pKb values of 10.2 and 9.9, respectively, actions mimicked by the novel antagonist, SB399,885 (10.9). SB271,046 likewise blocked partial agonist properties of WAY181,187 and WAY208,466 with pKb values of 9.8 and 9.0, respectively. 5-HT-stimulated [35S]GTP gamma S binding to G alpha s was antagonised by various antipsychotics including olanzapine (7.8), asenapine (9.1) and SB737,050 (7.8), whereas aripiprazole and bifeprunox were inactive. Further, antagonist properties of clozapine (8.0) were mimicked by its major metabolite, N-desmethylclozapine (7.9). In conclusion, the novel ligands, WAY208,466 and WAY181,187, behaved as partial agonists at 5-HT6 receptors coupled to G alpha s, while SB399,885 was a potent antagonist. Though 5-HT6 receptor blockade is not indispensable for therapeutic efficacy, it may well play a role in the functional actions of certain antipsychotic agents. [PubMed Citation] [Order full text from Infotrieve]

15) Kim HJ, Yun HM, Kim T, Nam G, Roh EJ, Kostenis E, Choo HY, Pae AN, Rhim H
Functional human 5-HT6 receptor assay for high throughput screening of chemical ligands and binding proteins.
Comb Chem High Throughput Screen. 2008 May;11(4):316-24.
Continuous identification and validation of novel drug targets require the development of rapid, reliable, and sensitive cell-based high-throughput screening (HTS) methods for proposed targets. Recently, the 5-HT(6) receptor (5-HT(6)R), a member of the class of recently discovered 5-HT receptors, has received considerable attention for its possible implications in depression, cognition, and anxiety. However, the cellular signaling mechanisms of 5-HT(6)R are poorly understood due to the lack of selective 5-HT(6)R ligands. In the present study, we examined functional coupling of the human 5-HT(6)R, 5-HT(7A)R, or 5-HT(7B)R with various Galpha-proteins (Galpha(15), Galpha(qs5), or Galpha(qG66Ds5)) to develop a reliable cell-based HTS method for 5-HT receptors. Among variable couplings between 5-HT receptors and G-proteins, we found that functional coupling of human 5-HT(6)R with Galpha(qG66Ds5) produced the highest levels of Ca(2+) signaling in HEK293 cells as measured by the fluorescence-based HTS plate reader, FDSS6000. After validation of this new 5-HT(6)R HTS system (Z'-factor = 0.56) in 96-well plates and characterization of the pharmacological profile of the 5-HT(6)R, we screened approximately 500 synthetic chemical compounds including butanamide and benzenesulfonamide derivatives. Based on this preliminary screening, we found that the butanamide derivative LSG11104 produced an IC(50) value of 6.3 microM. This compound will serve as a lead structure for further chemical modification to develop novel 5-HT(6)R ligands. Furthermore, we demonstrated that this HTS method can be utilized to identify proteins that modulate 5-HT(6)R function and present Fyn tyrosine kinase as an example, which is already known as a 5-HT(6)R interacting protein. Taken together, these results suggest that the 5-HT(6)R/Galpha(qG66Ds5) FDSS6000 system can be utilized to screen for selective 5-HT(6)R ligands and to examine any functional relationships between 5-HT(6)R and its binding proteins. [PubMed Citation] [Order full text from Infotrieve]

16) Foley AG, Hirst WD, Gallagher HC, Barry C, Hagan JJ, Upton N, Walsh FS, Hunter AJ, Regan CM
The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats.
Neuropharmacology. 2008 Jun;54(8):1166-74.
While there is now substantial evidence that 5-HT(6) antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT(6) receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT(6) receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits. [PubMed Citation] [Order full text from Infotrieve]

17) Alex K, Schwarz N, Khedkar V, Sayyed IA, Tillack A, Michalik D, Holenz J, D�az JL, Beller M
Synthesis of 3-(2-N,N-diethylaminoethoxy)indoles as potential 5-HT6 receptor ligands.
Org Biomol Chem. 2008 May 21;6(10):1802-7.
The synthesis of new pharmaceutically interesting 3-(2-N,N-diethylaminoethoxy)indole derivatives is described. Starting from 3-silyloxy-2-methylindoles, deprotection and in situ aminoalkylation provided 3-(2-N,N-diethylaminoethoxy)indoles in good yield. Further sulfonylation of these novel indoles gave access to potential 5-HT(6) receptor ligands. [PubMed Citation] [Order full text from Infotrieve]

18) Holmes A
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease.
Neurosci Biobehav Rev. 2008;32(7):1293-314.
The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research. [PubMed Citation] [Order full text from Infotrieve]

19) Shahid M, Walker GB, Zorn SH, Wong EH
Asenapine: a novel psychopharmacologicagent with a unique human receptor signature.
J Psychopharmacol. 2008 Feb 28;
Asenapine is a novel psychopharmacologic agent under development forthe treatment of schizophrenia and bipolar disorder. We determinedand compared the human receptor binding affinities and functionalcharacteristics of asenapine and several antipsychotic drugs. Compoundswere tested under comparable assay conditions using cloned humanreceptors. In comparison with the antipsychotics, asenapine showed highaffinity and a different rank order of binding affinities (pKi) for serotoninreceptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8],5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors(alpha1 [8.9],alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors(D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors(H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi<5) formuscarinic receptors and was the only agent with affinity for H2 receptors.Relative to its D2 receptor affinity, asenapine had a higher affinity for5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6,alpha2B and D3 receptors, suggestingstronger engagement of these targets at therapeutic doses. Asenapinebehaved as a potent antagonist (pKB) at 5-HT1A (7.4), 5-HT1B (8.1),5-HT2A (9.0), 5-HT2B (9.3), 5-HT2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2(9.1), D3 (9.1), alpha2A (7.3),alpha2B (8.3), alpha2C (6.8) and H1 (8.4) receptors.These functional effects differed from those of risperidone (pKBalpha5 for5-HT6) and olanzapine (pKB <5 for 5-HT1A and alpha2). Our results indicatethat asenapine has a unique human receptor signature, with bindingaffinity and antagonistic properties that differ appreciably from thoseof antipsychotic drugs. [PubMed Citation] [Order full text from Infotrieve]

20) Morairty SR, Hedley L, Flores J, Martin R, Kilduff TS
Selective 5HT2A and 5HT6 receptor antagonists promote sleep in rats.
Sleep. 2008 Jan 1;31(1):34-44.
STUDY OBJECTIVES: Serotonin (5-HT) has long been implicated in the control of sleep and wakefulness. This study evaluated the hypnotic efficacy of the 5-HT6 antagonist RO4368554 (RO) and the 5-HT2A receptor antagonist MDL100907 (MDL) relative to zolpidem. DESIGN: A randomized, repeated-measures design was utilized in which Wistar rats received intraperitoneal injections of RO (1.0, 3.0, and 10 mg/kg), MDL (0.1, 1.0 and 3.0 mg/kg), zolpidem (10 mg/kg), or vehicle in the middle of the dark (active) period. Electroencephalogram, electromyogram, body temperature (Tb) and locomotor activity were analyzed for 6 hours after injection. MEASUREMENTS AND RESULTS: RO, MDL, and zolpidem all produced significant increases in sleep and decreases in waking, compared with vehicle control. All 3 doses of MDL produced more consolidated sleep, increased non-rapid eye movement sleep (NREM) sleep, and increased electroencephalographic delta power during NREM sleep. The highest dose of RO (10.0 mg/kg) produced significant increases in sleep and decreases in waking during hour 2 following dosing. These increases in sleep duration were associated with greater delta power during NREM sleep. ZO Zolpidem induced sleep with the shortest latency and significantly increased NREM sleep and delta power but also suppressed rapid eye movement sleep sleep; in contrast, neither RO nor MDL affected rapid eye movement sleep. Whereas RO did not affect Tb, both zolpidem and MDL reduced Tb relative to vehicle-injected controls. CONCLUSIONS: These results support a role for 5-HT2A receptor modulation in NREM sleep and suggest a previously unrecognized role for 5-HT6 receptors in sleep-wake regulation. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]