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) Kishi T, Fukuo Y, Okochi T, Kawashima K, Kitajima T, Inada T, Ozaki N, Musso GM, Kane JM, Correll CU, Iwata N
Serotonin 6 receptor gene and schizophrenia: case-control study and meta-analysis.
Hum Psychopharmacol. 2012 Jan;27(1):63-9.
[PubMed Citation] [Order full text from Infotrieve]

2) Morozova MA, Beniashvili AG, Lepilkina TA, Rupchev GE
Double-blind placebo-controlled randomized efficacy and safety trial of add-on treatment of dimebon plus risperidone in schizophrenic patients during transition from acute psychotic episode to remission.
Psychiatr Danub. 2012 Jun;24(2):159-66.
[PubMed Citation] [Order full text from Infotrieve]

3) Nonogaki K
Serotonin conflict in sleep-feeding.
Vitam Horm. 2012;89:223-39.
Short sleep duration has been suggested to be a risk factor for weight gain and adiposity. Serotonin (5-HT) substantially contributes to the regulation of sleep and feeding behavior. Although 5-HT predominately promotes waking and satiety, the effects of 5-HT depend on 5-HT receptor function. The 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors reportedly contribute to sleep-waking regulation, whereas the 5-HT1B and 5-HT2C receptors contribute to the regulation of satiety. The 5-HT1B and 2C receptors may therefore be involved in the regulation of sleep-feeding. In genetic studies, 5-HT1B receptor mutant mice display greater amounts of rapid eye movement sleep (REMS) than wild-type mice, while displaying no effects on waking or slow wave sleep (SWS). On the other hand, 5-HT2C receptor mutant mice exhibit increased wakefulness and decreased SWS, without any effect on REMS. Moreover, the 5-HT2C receptor mutants display leptin-independent hyperphagia, leading to a middle-aged onset of obesity, whereas 5-HT1B receptor mutants do not display any effect on food intake. Thus, the genetic deletion of 5-HT2C receptors results in sleep loss-associated hyperphagia, leading to the late onset of obesity. This is a quite different pattern of sleep-feeding behavior than is observed in disturbed leptin signaling, which displays an increase in sleep-associated hyperphagia. In pharmacologic studies, 5-HT1B and 5-HT2C receptors upregulate wakefulness and downregulate SWS, REMS, and food intake. These findings suggest that 5-HT1B/2C receptor stimulation induces sleep loss-associated anorexia. Thus, the central 5-HT regulation of sleep-feeding can be dissociated. Functional hypothalamic proopiomelanocortin and orexin activities may contribute to the dissociated 5-HT regulation. [PubMed Citation] [Order full text from Infotrieve]

4) Shpakova EA, Skvortsova EA, Tarasenko II, Shpakov AO
[The secondary structure of peptides derived from the third intracellular loop of the serpentine type receptors and its interrelation with their biological activity].
Tsitologiia. 2012;54(2):119-29.
We and other authors have shown that synthetic peptides corresponding to regions of the third intracellular loop (ICL-3) of receptors of the serpentine type are capable of activating G-protein signaling cascades and trigger them in the absence of hormone. To create on the basis of these peptides the selective regulators of hormonal signaling systems the relationship between their biological activity and secondary structure are studied. It is assumed that most suitable is a helical conformation, which allows the peptide effectively interact with signaling proteins. The aim of this study was to test the biological activity and secondary structure of synthesized by us linear peptides and their dimeric and palmitoylated analogs, corresponding to C-terminal region of the ICL-3 of luteinizing hormone receptor (LHR) and 5-hydroxytryptamine receptor of the type 6 (5-HT6R). It is shown that LHR-peptides at the micromolar concentrations stimulate the basal activity of adenylyl cyclase (AC) and the GTP-binding of G-proteins in the plasma membranes of rat testes, while 5-HT6R-peptides activate AC and G-proteins in the synaptosomal membranes of rat brain. The action of peptides is tissue-specific and observed in the tissues where there are homologous receptors. The most effective were palmitoylated peptides. LHR-peptide reduced the AC stimulatory effect of human chorionic gonadotropin, while 5-HT6R-peptides the effect of 5-HT6R-agonist, EMD-386088, and the action of the peptides was not found in the case of non-homologous receptors. Using circular dichroism spectroscopy it is shown that in neutral (pH 7) and acidic (pH 2) medium all the peptides are exist predominantly in the antiparallel beta-sheet (37-42%) and disordered conformations (33-35%). In alkaline medium (pH 10) in the case palmitoylated peptides the increase of the contribution of the helical conformation to 12-27% was observed. In the presence of trifluoroethanol (10-80%), a helix-forming solvent, the contribution of helical conformation for the majority of peptides was slightly increased (for palmitoylated analogs to 14%), however, in this case the antiparallel beta-sheet and disordered conformation prevailed. The conclusion was made that the lack of clearly expressed ability to form helices in peptides derived the ICLs of receptors did not significantly affect their activity. This is consistent with proposed mechanism of peptides action, whereby peptide interacts with the complementary regions of homologous receptor that does not require the helix formation. [PubMed Citation] [Order full text from Infotrieve]

5) Chopra A, Tatara A, Shimizu S, Shin N, Sato M, Sugiuchi T, Imaki J, Ohno Y
Modulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders.
Prog Neuropsychopharmacol Biol Psychiatry. 2004;38(2):252-9.
Serotonin (5-hydroxytryptamine; 5-HT), a derivative of the tryptophan amino acid, is a low molecular weight neurotransmitter that plays an important role in the functioning of different physiological, cognitive, and emotional processes. Impairment of the serotonergic system is associated with psychiatric disorders, such as anxiety and depression, and neurological afflictions, such as Parkinson?s disease, Alzheimer?s disease, and epilepsy (1). The 5-HT mediates its biological activity through a group of seven receptors (5-HT1-7R) that are further classified into 14 distinct subtypes on the basis of their structure and pharmacological activity. Except for the 5-HT3R, which is a ligand-gated ion channel, all other 5-HTRs belong to the family of G-protein?coupled seven-transmembrane receptors (2). Radiolabeled tracers have been developed for use with positron emission tomography (PET) to study the different 5-HTR subtypes, and much information is available regarding only the 5-HT1AR, 5-HT1BR, 5-HT2AR, and 5-HT4R subtypes (3). Compared to the discovery of the other 5-HTR subtypes, the identification of 5-HT6R is fairly recent, and this receptor is located mostly in the limbic and cortical regions of the mammalian central nervous system (4). Although the exact mechanism of action of the 5-HT6R is not clear, there are indications that antagonists of this receptor reverse amnesia and improve cognitive and memory functions in individuals suffering from schizophrenia, Parkinson's disease, or Alzheimer?s disease (5). Therefore, it was imperative to develop a ligand that could be used to study the biological characteristics of this receptor. Radioiodinated SB-258585 ([125I]-SB258585), a selective antagonist of the 5-HT6R, has been shown to have a high affinity for this receptor in membranes derived from rat or pig striatum and human caudate putamen (6). Autoradiography of rat brain sections exposed to [125I]-SB258585 revealed that the 5-HT6R was located primarily in the striatum, followed by the cerebral cortex; accumulation was lowest in the cerebellum of these animals. From this observation, the investigators concluded that the receptor was probably involved in cognition, memory, and locomotor control functions in the animals (7). In another study, [N-methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline (GSK215083) was reported to have a 5-fold and >55-fold higher subnanomolar concentration affinity for the 5-HT6R compared to the concentrations required for the 5-HT2AR and the other 5-HTRs, respectively (3). In addition, the lipophilicity of GSK215083 was determined to be suitable for crossing the blood?brain barrier and penetration into the brain. On the basis of these observations, [11C]-GSK215083 was evaluated in vivo as a 5-HT6R ligand in pigs, non-human primates, and humans (3). [PubMed Citation] [Order full text from Infotrieve]

6) Da Silva Costa-Aze V, Quiedeville A, Boulouard M, Dauphin F
5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice.
Psychopharmacology (Berl). 2012 Aug 7;222(1):99-115.
[PubMed Citation] [Order full text from Infotrieve]

7) Henderson AJ, Guzzo PR, Ghosh A, Kaur J, Koo JM, Nacro K, Panduga S, Pathak R, Shimpukade B, Tan V, Xiang K, Wierschke JD, Isherwood ML
Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists.
Bioorg Med Chem Lett. 2012 Jul;22(4):1494-8.
A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography. [PubMed Citation] [Order full text from Infotrieve]

8) Parker CA, Gunn RN, Rabiner EA, Slifstein M, Comley R, Salinas C, Johnson CN, Jakobsen S, Houle S, Laruelle M, Cunningham VJ, Martarello L
Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor.
J Nucl Med. 2012 Feb 15;53(2):295-303.
[PubMed Citation] [Order full text from Infotrieve]

9) Yun HM, Rhim H
5-HT6 receptor ligands, EMD386088 and SB258585, differentially regulate 5-HT6 receptor-independent events.
Toxicol In Vitro. 2012 Feb;25(8):2035-40.
The serotonin 6 receptor (5-HT6R) is one of the most recently cloned receptors among the known serotonin receptors. Because it is abundantly distributed in the limbic region and is involved in neurological disorders, it has generated much interest as a drug discovery and a biological research target. However, several groups recently reported conflicting results for 5-HT6R ligands in animal studies. Herein, we investigated in vitro effects of 5-HT6R ligands in cultured neurons and mammalian cell lines to explain inconsistencies in the results of in vivo studies. When examined the effects of EMD386088, a 5-HT6R agonist, on cell viability, we found that EMD386088 potentiated cell death in cultured neuronal, native HEK293, and HEK/HA-5-HT6R cells. The results demonstrated that EMD386088 induces its cytotoxic effects, regardless of the presence of 5-HT6Rs, by the downregulation of ERK1/2 activities. Furthermore, we studied the 5-HT6R-independent effects of SB258585, a specific 5-HT6R antagonist. SB258585 potentiated cell death and induced an increase in [Ca2+]i, whereas EMD386088 or 5-HT did not affect [Ca2+]i. Because EMD386088 and SB258585 have been intensively used as 5-HT6R ligands in in vitro and in vivo studies, our findings suggest that these compounds should be used with caution in cell-based studies as well as behavioral studies. [PubMed Citation] [Order full text from Infotrieve]

10) Liu F, Majo VJ, Prabhakaran J, Milak MS, John Mann J, Parsey RV, Kumar JS
Synthesis and in vivo evaluation of [O-methyl-11C] N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide as an imaging probe for 5-HT6 receptors.
Bioorg Med Chem. 2011 Dec;19(17):5255-9.
The serotonin receptor 6 (5-HT(6)) is implicated in the pathophysiology of cognitive diseases, schizophrenia, anxiety and obesity and in vivo studies of this receptor would be of value for studying the pathophysiology of these disorders. Therefore, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB399885), a selective and high affinity (pK(i)=9.11) 5-HT(6) antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue with [(11)C]MeOTf in order to determine the suitability of [(11)C]SB399885 to quantify 5-HT(6)R in living brain using PET. Desmethyl-SB399885 was prepared, starting from 1-(2-methoxyphenyl) piperazine hydrochloride, in excellent yield. The yield obtained for radiolabeling of [(11)C]SB399885 was 30�5% (EOS) and the total synthesis time was 30min at EOB. PET studies with [(11)C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [(11)C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [(11)C]SB399885 compared to known 5-HT(6)R distribution limits its usefulness for the in vivo quantification of 5-HT(6)R with PET. [PubMed Citation] [Order full text from Infotrieve]

11) Nirogi RV, Kambhampati R, Kothmirkar P, Konda J, Bandyala TR, Gudla P, Arepalli S, Gangadasari NP, Shinde AK, Deshpande AD, Dwarampudi A, Chindhe AK, Dubey PK
Synthesis and structure-activity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands.
J Enzyme Inhib Med Chem. 2011 Sep 1;27(3):443-50.
5-Hydroxytryptamine 6 receptors (5-HT(6)R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure-activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT(6) receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT(6)R with the K(i) of 23.4 and 20.5?nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze. [PubMed Citation] [Order full text from Infotrieve]

12) de Bruin NM, Prickaerts J, van Loevezijn A, Venhorst J, de Groote L, Houba P, Reneerkens O, Akkerman S, Kruse CG
Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats.
Neurobiol Learn Mem. 2012 Jun;96(2):392-402.
The 5-hydroxytryptamine(6) (5-HT(6)) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT(6) antagonists compound (CMP) X and CMP Y and the reference 5-HT(6) antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept�, approved for symptomatic treatment of Alzheimer's disease, AD) was used as a positive reference compound. First, effects of the 5-HT(6) antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT(6) antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT(6) antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine. Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT(6) antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT. In conclusion, the 5-HT(6) antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT(6) receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil. [PubMed Citation] [Order full text from Infotrieve]

13) Nirogi R, Dwarampudi A, Kambhampati R, Bhatta V, Kota L, Shinde A, Badange R, Jayarajan P, Bhyrapuneni G, Dubey PK
Rigidized 1-aryl sulfonyl tryptamines: synthesis and pharmacological evaluation as 5-HT6 receptor ligands.
Bioorg Med Chem Lett. 2011 Sep;21(15):4577-80.
A series of N(1)-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N(1)-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT(6) receptor. Several compounds displayed potent binding affinity for the 5-HT(6) receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C(3) of indole carbon maintains the binding affinity to 5-HT(6)R. The lead compound N(1)-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (K(b)=0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze. [PubMed Citation] [Order full text from Infotrieve]

14) Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, De Ronchi D, Serretti A
Pharmacogenetics of antidepressants.
Front Pharmacol. 2011 Aug 1;2:6.
Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O-methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene?�?environment interactions have been hypothesized to modulate several of these effects. [PubMed Citation] [Order full text from Infotrieve]

15) Marazziti D, Baroni S, Catena Dell'Osso M, Bordi F, Borsini F
Serotonin receptors of type 6 (5-HT6): what can we expect from them?
Curr Med Chem. 2011;18(18):2783-90.
The serotonin (5-HT) receptors of type 6 (5-HT6) are relatively new. They are quite different from all other 5-HT receptors, as they are characterized by a short third cytoplasmatic loop and a long C-terminal tail, and contain one intron located in the middle of the third cytoplasmatic loop. After some initial controversies, the available findings are now apparently more congruent. Nevertheless, discrepancies still exist, such as those in binding affinity, effects of 5-HT6 ligands on brain catecholamines and behavioral syndromes mediated by them. Much interest in 5-HT6 receptors was triggered by the evidence that some antipsychotics could bind to them. Subsequently, despite the lack of complete information on metabolic patterns of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic and anti-obese drugs. In any case, the available information on both the pharmacology of 5-HT6 receptors is still quite scant. Therefore, with the present paper we aimed at reporting a comprehensive review on the status of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists. [PubMed Citation] [Order full text from Infotrieve]

16) Tassone A, Madeo G, Schirinzi T, Vita D, Puglisi F, Ponterio G, Borsini F, Pisani A, Bonsi P
Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission.
Neuropharmacology. 2011;61(4):632-7.
We investigated the effect of 5-HT6 receptor subtype activation on glutamatergic transmission by means of whole-cell patch-clamp electrophysiological recordings from medium spiny neurons of the striatum and layer V pyramidal neurons of the prefrontal cortex. To this aim, we took advantage of a novel ligand, ST1936, showing nM affinity and agonist activity at the 5-HT6 receptor subtype. Our data show that 5-HT6 receptor activation by ST1936 reduces the frequency of spontaneous excitatory postsynaptic currents, with an IC50 of 1.3 ?M. Moreover, 5-HT6 receptor activation also reduced the amplitude of spontaneous excitatory postsynaptic currents recorded from medium spiny neurons, suggesting a mechanism of action involving postsynaptic 5-HT6 receptors, as further confirmed by the paired-pulse analysis on evoked excitatory postsynaptic currents and by recordings of miniature glutamatergic events. The inhibitory effect of ST1936 on glutamatergic transmission was prevented by the selective 5-HT6 receptor antagonist SB258585 and mimicked by a different agonist, WAY-181187. Conversely, in the cortex ST1936 reduced the frequency, but not the amplitude, of spontaneous excitatory postsynaptic currents suggesting a presynaptic or indirect effect of the 5-HT6 receptor. [PubMed Citation] [Order full text from Infotrieve]

17) Riccioni T, Bordi F, Minetti P, Spadoni G, Yun HM, Im BH, Tarzia G, Rhim H, Borsini F
ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors.
Eur J Pharmacol. 2011 Sep;661(1-3):8-14.
5-HT(6) receptor is one of the most recently cloned serotonin receptors, and it might play important roles in Alzheimer's disease, depression, and learning and memory disorders. Availability of only very few 5-HT(6) receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT(6) receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT(6) receptors with good affinity (K(i)=28.8 nM). ST1936 also exhibited some moderate binding affinity for 5HT(2B), 5HT(1A), 5HT(7) receptors and adrenergic ? receptors. ST1936 behaved as a full 5-HT(6) agonist on cloned cells and was able to increase Ca(2+) concentration, phosphorylation of Fyn kinase, and regulate the activation of ERK1/2 that is a downstream target of Fyn kinase. These effects were completely antagonized by two 5-HT(6) receptor antagonists, SB271046 and SB258585. The other 5-HT(6) receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT(6) receptor-dependent signal pathways, such as cAMP, Fyn and ERK1/2 kinase, as specific agonists. [PubMed Citation] [Order full text from Infotrieve]

18) Nirogia RV, Kambhampati R, Daulatabad AV, Gudla P, Shaikh M, Achanta PK, Shinde AK, Dubey PK
Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands.
J Enzyme Inhib Med Chem. 2011 Jul 1;26(3):341-9.
A series of novel conformationally restricted N(1)-arylsulfonyl-3-aminoalkoxy indoles were designed and synthesized as 5-HT(6) receptor (5-HT(6)R) ligands. Many of the synthesized compounds have moderate in vitro-binding affinities at 5-HT(6)R. The lead compound 8b (% inhibition?=?97.2 at 1 ?M) from this series has good pharmacokinetic profile in male Wister rats and is active in animal model of cognition like Morris water maze. The details of chemistry, SAR, pharmacokinetics and pharmacological data constitute the subject matter of this report. [PubMed Citation] [Order full text from Infotrieve]

19) Nikiforuk A, Kos T, Wesołowska A
The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effects in rats after intrahippocampal administration.
Psychopharmacology (Berl). 2011 Jun;217(3):411-8.
[PubMed Citation] [Order full text from Infotrieve]