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) 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]

2) 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]

3) Holmes A
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease.
Neurosci Biobehav Rev. 2008 Mar 26;
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]

4) 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]

5) 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. [PubMed Citation] [Order full text from Infotrieve]

6) Dukat M, Mosier PD, Kolanos R, Roth BL, Glennon RA
Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies.
J Med Chem. 2008 Feb 14;51(3):603-11.
A population of 100 graphics models of the human 5-HT6 serotonin receptor was constructed based on the structure of bovine rhodopsin. The endogenous tryptamine-based agonist serotonin (5-HT; 1) and the benzenesulfonyl-containing tryptamine-derived 5-HT6 receptor antagonist MS-245 (4a) were automatically docked with each of the 100 receptor models using a genetic algorithm approach. Similar studies were conducted with the more selective 5-HT6 receptor agonist EMDT (5) and optical isomers of EMDT-related analog 8, as well as with optical isomers of MS-245 (4a)-related and benzenesulfonyl-containing pyrrolidine 6 and aminotetralin 7. Although associated with the same general aromatic/hydrophobic binding cluster, 5-HT (1) and MS-245 (4a) were found to preferentially bind with distinct receptor conformations, and did so with different binding orientations (i.e., poses). A 5-HT pose/model was found to be common to EMDT (5) and its analogs, whereas that identified for MS-245 (4a) was found common to benzenesulfonyl-containing compounds. Specific amino acid residues were identified that can participate in binding, and evaluation of a sulfenamide analog of MS-245 indicates for the first time that the presence of the sulfonyl oxygen atoms enhances receptor affinity. The results indicate that the presence or absence of an N1-benzenesulfonyl group is a major determinant of the manner in which tryptamine-related agents bind at 5-HT6 serotonin receptors. [PubMed Citation] [Order full text from Infotrieve]

7) Lane HY, Liu YC, Huang CL, Hsieh CL, Chang YL, Chang L, Chang YC, Chang WH
Prefrontal executive function and D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy adults.
J Psychiatry Neurosci. 2008 Jan;33(1):47-53.
OBJECTIVE: The Val158Met polymorphism of the catechol-O-methyltransferase gene has been demonstrated to be associated with prefrontal executive function explaining 4% of variance in perseverative errors on the Wisconsin Card Sorting Test (WCST). Studies suggest that dopamine D(1) and D(3) and serotonin 5-HT(2A) and 5-HT(6) receptors may also be involved in prefrontal cognitive function and that genetic polymorphisms (D(1) A-48G, D(3) Ser9Gly, 5-HT(2A) T102C, and 5-HT(6) T267C) of these receptors may be associated with brain glucose metabolism or neurophysiological function. The current study's objective was to investigate whether executive function varies with these genetic variations. METHODS: A sample of 216 healthy Han Chinese adults were measured with the WCST and genotyped for the 4 genetic polymorphisms. RESULTS: Kruskal-Wallis tests showed a significant difference in WCST perseverative errors among the genotypes D(3) Ser9Gly (p = 0.009), 5-HT(2A) T102C (p = 0.038) and 5-HT(6) T267C (p = 0.010), but not in the genotype D(1) A-48G. Multiple regression analysis for the WCST natural logarithm values (i.e., for fulfilling the normal distribution requirement) showed that subjects' perseverative errors were significantly influenced by D(1) A-48G, D(3) Ser9Gly, 5-HT(2A) T102C and 5-HT(6) T267C polymorphisms after adjustment of other variables. CONCLUSION: The preliminary data suggest that D(1), D(3), 5-HT(2A) and 5-HT(6) genetic mutations may influence prefrontal executive cognition in healthy adults. Further studies in larger samples with other ethnicities or in mentally ill patients are warranted. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

8) Wesołowska A
Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats.
Pharmacol Rep. 2007 Nov-Dec;59(6):664-71.
The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(6) (5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885) was studied in the forced swim test in rats. SB-399885 administered intraperitoneally at a single dose of 10 mg/kg potently shortened the immobility time in rats. That potential antidepressant-like effect of SB-399885 was not modified in animals with a lesion of the 5-HT system produced by p-chloroamphetamine (p-CA, 2 x 10 mg/kg). The anti-immobility effect of SB-399885 was blocked by the dopamine D(1)- and D(2)-like receptor antagonists SCH 23390 (0.063 mg/kg) and sulpiride (10 mg/kg), respectively, as well as by the alpha(2)-adrenoceptor antagonist idazoxan (4 mg/kg), but it was not changed by the alpha(1)-adrenoceptor antagonist prazosin (1 mg/kg). Neither sulpiride (10 mg/kg) or idazoxan (4 mg/kg) nor SCH-23390 (0.063 mg/kg) administered jointly with SB-399885 (10 mg/kg) noticeably changed the exploratory locomotor activity of rats evaluated by the open field test. The results described in the present paper indicate that the anti-immobility activity of SB-399885 is not connected with 5-HT innervation, and that D(1)- and D(2)-like receptors and alpha(2)-adrenoceptors are involved in this action. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

9) Wesołowska A
The anxiolytic-like effect of the selective 5-HT6 receptor antagonist SB-399885: the impact of benzodiazepine receptors.
Eur J Pharmacol. 2008 Feb 12;580(3):355-60.
The effect of lesion of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 mg/kg), and the influence of the benzodiazepine receptor antagonist flumazenil (10 mg/kg) on the anticonflict action of N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), a selective 5-HT6 receptor antagonist, were investigated in the Vogel conflict drinking test in rats. In addition, the interaction between SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) was evaluated in that test. All the compounds tested were administered intraperitoneally. The anticonflict activity produced by SB-399885 (3 mg/kg) was not modified in p-CA-pretreated rats, but it was totally blocked by flumazenil. Combined administration of non-active doses of SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) produced a pronounced anticonflict effect in rats. The present results suggest that the anticonflict activity of SB-399885 is not conditioned by the integrity of 5-HT neurons, and that benzodiazepine receptors are indirectly involved in its effect, possibly due to a functional interaction between 5-HT6 receptors and the gamma-aminobutyric acid (GABA)/benzodiazepine system. [PubMed Citation] [Order full text from Infotrieve]

10) Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H
Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders.
Pharmacol Ther. 2008 Feb;117(2):207-31.
The increasing global prevalence of obesity unequivocally demonstrates that neither behavioural (diet and exercise) nor pharmacological approaches to this health problem are working. In this area of high unmet clinical need, the 5-HT6 receptor has generated enormous interest amongst academic and pharmaceutical industry scientists as a molecular target for the development of a new generation of safe and more effective anti-obesity drugs. In this review, we have described the major developments that have occurred in the fields of the medicinal chemistry and pharmacology of 5-HT6 ligands, with particular emphasis on their potential application as novel anti-obesity drugs. The last 5 years have witnessed an increasing understanding of the 5-HT6 receptor and its structural requirements that has produced an explosion in the number and diversity of novel, highly selective 5-HT6 receptor agonists, partial agonists and antagonists that have been designed and synthesized. In animal models, 5-HT6 receptor ligands of all functional types have been shown to decrease food intake when given acutely and chronically, to evoke profound and sustained weight-loss in obese animals, and concomitantly to improve a number of cardio-metabolic risk factors. Comparator studies in obese animal models, which are highly predictive of clinical outcomes, indicate that 5-HT6 ligands may have the potential to be more efficacious in the treatment of obesity than the current generation of anti-obesity drugs. [PubMed Citation] [Order full text from Infotrieve]

11) Seong CM, Park WK, Park CM, Kong JY, Park NS
Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists.
Bioorg Med Chem Lett. 2008 Jan 15;18(2):738-43.
A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT(6) antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT(6) receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K(i)=12.3 nM) for 5-HT(6) receptor with good selectivity over other serotonin and dopamine (D(1)-D(4)) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC(50)=0.61 microM). [PubMed Citation] [Order full text from Infotrieve]

12) Kim HJ, Doddareddy MR, Choo H, Cho YS, No KT, Park WK, Pae AN
New serotonin 5-HT(6) ligands from common feature pharmacophore hypotheses.
J Chem Inf Model. 2008 Jan;48(1):197-206.
Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimer's disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commercially available database. A three-dimensional common feature pharmacophore model was developed by using the HipHop program provided in Catalyst software and was used as a query for screening the database. A recursive partitioning (RP) model which can separate active and inactive compounds was used as a filtering system. Finally a sequential virtual screening procedure (SQSP) was conducted, wherein both the common feature pharmacophore and the RP model were used in succession to improve the results. Some of the hits were selected based on druglikeness, ADME properties, structural diversity, and synthetic accessibility for real biological evaluation. The best hit compound showed a significant IC50 value of 9.6 nM and can be used as a lead for further drug development. [PubMed Citation] [Order full text from Infotrieve]

13) Tang S, Verdurand M, Joseph B, Lemoine L, Daoust A, Billard T, Fournet G, Le Bars D, Zimmer L
Synthesis and biological evaluation in rat and cat of [18F]12ST05 as a potential 5-HT6 PET radioligand.
Nucl Med Biol. 2007 Nov;34(8):995-1002.
INTRODUCTION: 5-hydroxytryptamine (5-HT)6 receptors represent one of the more recently discovered serotoninergic receptor family. However, no 5-HT6 positron emission tomography (PET) radiotracer is currently used in clinical imaging studies. The purpose of this study was to propose the first fluorinated PET radiotracer for this brain receptor. METHODS: A new compound presenting in vitro high affinity towards the serotoninergic 5-HT6 receptor, N-[2-(1-[(4-fluorophenyl)sulfonyl]-1H-indol-4-yloxy)ethyl]-N,N-dimethylamine, was labelled with fluorine 18 via a nitro-/fluoronucleophilic substitution. Biological evaluations included (i) in vitro and ex vivo autoradiographies in rat brain and (ii) a PET scan on anaesthetized cat. RESULTS AND CONCLUSION: Although the radioligand showed excellent brain penetration, it did not reveal any specific binding to the 5-HT6 receptors indicating that this radiotracer is not suitable for mapping 5-HT6 receptors using PET. [PubMed Citation] [Order full text from Infotrieve]

14) Cole DC, Stock JR, Lennox WJ, Bernotas RC, Ellingboe JW, Boikess S, Coupet J, Smith DL, Leung L, Zhang GM, Feng X, Kelly MF, Galante R, Huang P, Dawson LA, Marquis K, Rosenzweig-Lipson S, Beyer CE, Schechter LE
Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist.
J Med Chem. 2007 Nov 15;50(23):5535-8.
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders. [PubMed Citation] [Order full text from Infotrieve]

15) Loiseau F, Dekeyne A, Millan MJ
Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex.
Psychopharmacology (Berl). 2008 Jan;196(1):93-104.
RATIONALE: 5-HT6 receptor antagonists improve cognitive processes in rodents. However, their site(s) of action remains unexplored and their influence upon social memory has been little investigated. OBJECTIVES: We examined the influence of 5-HT6 receptor ligands upon social memory in rats by use of systemic or local administration into the frontal cortex (FCX), striatum, or nucleus basalis magnocellularis (NBM). MATERIALS AND METHODS: The social recognition test is based upon the ability of an adult rat to recognize a younger conspecific during the second of two 5-min sessions. In a procedure without an inter-session interval, the actions of drugs alone and the ability to reverse "amnesia" induced by the muscarinic antagonist, scopolamine (1.25 mg/kg, s.c.), were examined. The potential promnesic effect of drugs was also investigated in another procedure where a spontaneous deficit of recognition was induced by a 120-min inter-session interval. RESULTS: The 5-HT6 receptor agonist, WAY-181187 (10.0 mg/kg, i.p.), significantly impaired social recognition. This effect was abolished by the 5-HT6 receptor antagonists, SB-271046 (20.0 mg/kg, i.p.) and SB-258585 (10.0 mg/kg, i.p.). These agents also abolished scopolamine-induced amnesia (10.0 and 2.5 mg/kg, i.p., respectively) and reversed the delay-induced deficit (10.0-20.0 and 2.5-10.0 mg/kg, i.p., respectively). WAY-181187 into the FCX significantly impaired social recognition (0.16-0.63 microg/side). Conversely, SB-271046 into the FCX (2.5-5.0 microg/side), but neither into the striatum nor the NBM, significantly reversed spontaneous deficit. CONCLUSION: These results indicate that 5-HT6 receptors modulate social recognition by actions in the FCX and underpin their pertinence as targets for the treatment of psychiatric disorders in which cognitive function is compromised. [PubMed Citation] [Order full text from Infotrieve]

16) Mitchell ES, Neumaier JF
5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine.
Pharmacol Biochem Behav. 2008 Jan;88(3):291-8.
5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped Fos induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased Fos expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders. [PubMed Citation] [Order full text from Infotrieve]

17) Tasler S, Kraus J, Wuzik A, M�ller O, Aschenbrenner A, Cubero E, Pascual R, Quintana-Ruiz JR, Dordal A, Merc� R, Codony X
Discovery of 5-HT6 receptor ligands based on virtual HTS.
Bioorg Med Chem Lett. 2007 Nov 15;17(22):6224-9.
Based on a pharmacophore alignment on a 5-HT(6) ligand applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)s down to 8 nM were achieved. [PubMed Citation] [Order full text from Infotrieve]

18) Wesołowska A, Nikiforuk A, Stachowicz K
Anxiolytic-like and antidepressant-like effects produced by the selective 5-HT6 receptor antagonist SB-258585 after intrahippocampal administration to rats.
Behav Pharmacol. 2007 Sep;18(5-6):439-46.
The purpose of this study was to investigate the effect of SB-258585, a selective 5-HT6 receptor antagonist, administered intrahippocampally to rats, in the conflict drinking and forced swim tests, that is models used for evaluating anxiolytic-like and antidepressant-like activity, respectively. Diazepam and imipramine were used as reference drugs. SB-258585 at a dose of 1 microg (but not 0.3 and 3 microg) showed an anticonflict effect that was weaker than that of diazepam (40 microg). SB-258585 at a dose of 3 microg (but not 1 and 10 microg) produced a marked anti-immobility effect comparable with that of imipramine (0.1 microg). The anxiolytic-like and antidepressant-like activity of SB-258585 seemed to be specific, as that compound--when given by the same route in doses effective in each model--did not affect the shock threshold, nonpunished water consumption, or exploratory activity of rats. The results obtained indicate that the hippocampus is one of the neuroanatomical sites involved in the anxiolytic-like and antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-258585. [PubMed Citation] [Order full text from Infotrieve]

19) Ferguson SM, Mitchell ES, Neumaier JF
Increased expression of 5-HT6 receptors in the nucleus accumbens blocks the rewarding but not psychomotor activating properties of cocaine.
Biol Psychiatry. 2008 Jan 15;63(2):207-13.
BACKGROUND: Repeated exposure to cocaine produces enduring forms of drug experience-dependent behavioral plasticity, including conditioned place preference (CPP) and psychomotor sensitization, a progressive and persistent increase in cocaine's psychomotor activating effects. Although serotonin-6 receptors (5-HT6Rs) are abundantly expressed in the brain regions thought to underlie these phenomena, such as the nucleus accumbens (NAc), surprisingly little is known about the role of 5-HT6Rs in the rewarding and psychomotor activating effects of cocaine. METHODS: Viral-mediated gene transfer was used to selectively increase 5-HT6R expression in the NAc of rats. The effects of 5-HT6R overexpression and the selective 5-HT6R antagonist Ro4368554 on CPP and psychomotor sensitization were examined. RESULTS: Increased expression of 5-HT6Rs in the NAc blocks a CPP to cocaine but has no effect on either the acute locomotor response to cocaine or on the development of cocaine-induced locomotor sensitization. Furthermore, antagonism of 5-HT6Rs facilitates the acquisition of a CPP to cocaine but has no effect on cocaine-induced stereotypy. CONCLUSIONS: These results demonstrate that 5-HT6Rs in the NAc can selectively modulate drug reward, possibly through facilitation of reward learning. [PubMed Citation] [Order full text from Infotrieve]

20) Schechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE
Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466.
Neuropsychopharmacology. 2008 May;33(6):1323-35.
One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT6 receptor and profile as full receptor agonists (WAY-181187: EC50=6.6 nM, Emax=93%; WAY-208466: EC50=7.3 nM; Emax=100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 microM), confirming a local relationship between 5-HT6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT(6) receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD). [PubMed Citation] [Order full text from Infotrieve]