Target Validation Information
Target ID T16691
Target Name 5-hydroxytryptamine 6 receptor
Target Type
Clinical Trial
Drug Potency against Target N,N-diethyl-2-(1H-indol-3-yl)ethanamine Drug Info Ki = 575 nM [1]
2-Benzyl-4-piperazin-1-yl-1H-benzimidazole Drug Info Ki = 31 nM [2]
5-MEO-DMT Drug Info Ki = 13 nM [1]
1-phenylthio-N,N-dimethyltryptamine Drug Info Ki = 90 nM [3]
6-(piperazin-1-yl)-3-tosyl-1H-indazole Drug Info Ki = 27 nM [4]
1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole Drug Info Ki = 1 nM [5]
5-(4-Methylpiperazin-1-yl)-3-tosyl-1H-indazole Drug Info IC50 = 112 nM [4]
E-6837 Drug Info Ki = 0.7 nM [6]
6-tosyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole Drug Info Ki = 29 nM [7]
4-(piperazin-1-yl)-1H-indole Drug Info Ki = 2700 nM [8]
4-(1H-indol-1-ylsulfonyl)benzenamine Drug Info Ki = 10 nM [8]
1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole Drug Info Ki = 1 nM [8]
4-(1H-Indol-3-ylmethyl)-phenylamine Drug Info Ki = 2530 nM [9]
N-(4-(2-aminoethyl)phenyl)benzenesulfonamide Drug Info Ki = 38 nM [10]
OCTOCLOTHEPIN Drug Info Ki < 50 nM [11]
4-(4-methoxy-1H-indol-1-ylsulfonyl)benzenamine Drug Info Ki = 3.3 nM [12]
4-(6-methoxy-1H-indol-1-ylsulfonyl)benzenamine Drug Info Ki = 1.8 nM [12]
[2-(3-Benzyl-3H-indol-1-yl)-ethyl]-dimethyl-amine Drug Info Ki = 6 nM [13]
2-Ethyl-5-methoxy-3-piperidin-4-yl-1H-indole Drug Info IC50 = 300 nM [14]
WAY-181187 Drug Info Ki = 2 nM [15]
3-(phenylsulfonyl)-1-(piperidin-4-yl)-1H-indole Drug Info Ki = 91 nM [16]
SPIPERONE Drug Info Ki = 1595 nM [17]
2-(1-tosyl-1H-indol-3-yl)ethanamine Drug Info Ki = 8 nM [18]
(+/-)-nantenine Drug Info Ki = 257 nM [19]
4-(piperazin-1-yl)-3-tosyl-1H-indazole Drug Info Ki = 134 nM [4]
Ro-04-6790 Drug Info Ki = 47 nM [6]
3-(2-Amino-ethyl)-2-methyl-1H-indol-5-ol Drug Info Ki = 400 nM [17]
Ro-63-0563 Drug Info Ki = 512 nM [20]
2-(1-benzyl-1H-inden-3-yl)-N,N-dimethylethanamine Drug Info Ki = 3 nM [6]
QUIPAZINE Drug Info Ki = 3600 nM [17]
[2-(3-Benzyl-3H-inden-1-yl)-ethyl]-methyl-amine Drug Info Ki = 3 nM [9]
4-(3H-Inden-1-ylmethyl)-phenylamine Drug Info Ki = 11800 nM [9]
2-(4-(benzenesulfonyl)phenyl)-1-aminoethane Drug Info Ki = 37 nM [10]
[2-(3-Benzyl-indol-1-yl)-ethyl]-dimethyl-amine Drug Info Ki = 32 nM [9]
4-(Indan-1-ylsulfanyl)-phenylamine Drug Info Ki = 4200 nM [9]
N-(3-(2-aminoethyl)phenyl)benzenesulfonamide Drug Info Ki = 21 nM [10]
4-(3-benzenesulfonamidophenyl)piperazine Drug Info Ki = 62 nM [10]
1-(2-Methoxy-phenyl)-piperazine Drug Info Ki = 1.2 nM [21]
N-(3-(3-aminopropyl)phenyl)benzenesulfonamide Drug Info Ki = 230 nM [10]
4-(4-benzenesulfonamidophenyl)piperazine Drug Info Ki = 85 nM [10]
N-(3-(aminomethyl)phenyl)benzenesulfonamide Drug Info Ki = 290 nM [10]
4-(3-benzenesulfonylphenyl)piperazine Drug Info Ki = 1.2 nM [10]
2-(3-phenylthio)phenyl)-1-aminoethane Drug Info Ki = 115 nM [10]
N-(3-aminophenyl)benzenesulfonamide Drug Info Ki = 2840 nM [10]
4-(4-benzenesulfonylphenyl)piperazine Drug Info Ki = 6.9 nM [10]
4-(2-benzenesulfonylphenyl)piperazine Drug Info Ki = 4000 nM [10]
4-Indan-1-ylmethyl-phenylamine Drug Info Ki = 6100 nM [9]
4-(4,6-dinitro-1H-indol-1-ylsulfonyl)benzenamine Drug Info Ki = 980 nM [8]
4-Inden-(1E)-ylidenemethyl-phenylamine Drug Info Ki = 640 nM [9]
EDMT Drug Info Ki = 16 nM [6]
4-((1H-indol-1-yl)methyl)benzenamine Drug Info Ki = 8200 nM [22]
N,N-dimethyl-2-(1-tosyl-1H-indol-3-yl)ethanamine Drug Info Ki = 2.5 nM [22]
DIMEBOLIN Drug Info Ki = 26 nM [23]
N-phenyl-3-(2-aminoethyl)benzenesulfonamide Drug Info Ki = 70 nM [10]
2-(3-benzenesulfonyl)phenyl-1-aminoethane Drug Info Ki = 50 nM [10]
5-METHOXYTRYPTAMINE Drug Info Ki < 50 nM [11]
SEROTONIN Drug Info IC50 = 27.5 nM [24]
METHIOTHEPIN Drug Info IC50 = 2.4 nM [24]
3-(phenylsulfonyl)-1-(pyrrolidin-3-yl)-1H-indole Drug Info Ki = 5 nM [16]
3-(phenylsulfonyl)-1-(piperidin-3-yl)-1H-indole Drug Info Ki = 13 nM [16]
SB-742457 Drug Info Ki = 0.25 nM [25]
5,6-dichloro-3,4-dihydroquinazolin-2-amine Drug Info Ki = 1157 nM [26]
SB-271046 Drug Info Ki = 0.66 nM [27]
1-(3-(benzyloxy)-2-methylphenyl)piperazine Drug Info Ki = 1.3 nM [27]
SB-357134 Drug Info Ki = 3 nM [20]
4-(Naphthalene-1-sulfonyl)-phenylamine Drug Info Ki = 34 nM [21]
4-(3-Methyl-indole-1-sulfonyl)-phenylamine Drug Info Ki = 12 nM [21]
WAY-466 Drug Info Ki = 1 nM [28]
1-Naphthalen-1-yl-piperazine Drug Info Ki = 100 nM [21]
4-(1H-Inden-1-ylmethyl)-phenylamine Drug Info Ki = 4470 nM [9]
4-(Indane-1-sulfonyl)-phenylamine Drug Info Ki = 740 nM [9]
2-(3-(phenylsulfonyl)-1H-indol-1-yl)ethanamine Drug Info Ki = 25 nM [29]
2-(1-benzyl-1H-indol-3-yl)-N,N-dimethylethanamine Drug Info Ki = 6 nM [6]
1-Benzenesulfonyl-3-piperidin-4-yl-1H-indole Drug Info IC50 = 19.5 nM [30]
WAY-208466 Drug Info Ki = 4.8 nM [29]
CHLOROPHENYLPIPERAZINE Drug Info Ki = 2300 nM [17]
2-(1-(phenylsulfonyl)-1H-indol-3-yl)ethanamine Drug Info Ki = 10 nM [18]
[2-(3H-Indol-1-yl)-ethyl]-dimethyl-amine Drug Info Ki = 1900 nM [13]
Action against Disease Model SB-742457 The effect of a selective 5-HT(6) receptor antagonist SB-742457 to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats was examined. The PCP-induced selective reversal learning deficit was significantly improved by SB-742457. [31] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations 5-HT6 receptors are the latest serotonin receptors to be identified by molecular cloning. Their high affinity for a wide range of drugs used in psychiatry, coupled with their intriguing distribution in the brain, has stimulated significant interest. Antisense oligonucleotides, antipeptide antibodies, selective radioligands, knockout mice, and selective antagonists of the 5-ht6 receptor have recently become available. 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. Furthermore, polymorphisms in the sequence of the 5-ht6 receptor gene may provide a genetic tool to further our understanding of the differential responses of patients to antipsychotic medications [1]
References
REF 1Bioorg Med Chem Lett. 2006 Nov 15;16(22):5832-5. Epub 2006 Aug 30.Interaction of N1-unsubstituted and N1-benzenesulfonyltryptamines at h5-HT6 receptors.
REF 2J Med Chem. 2010 Feb 11;53(3):1357-69.Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation.
REF 3J Med Chem. 2008 Feb 14;51(3):603-11. Epub 2008 Jan 18.Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies.
REF 4J Med Chem. 2010 Nov 11;53(21):7639-46.5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists.
REF 5Bioorg Med Chem Lett. 2005 Nov 1;15(21):4780-5.Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists.
REF 6J Med Chem. 2009 Feb 12;52(3):675-87.Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists.
REF 7Bioorg Med Chem Lett. 2008 Jul 15;18(14):3929-31. Epub 2008 Jun 13.A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands.
REF 8Bioorg Med Chem Lett. 2005 Dec 1;15(23):5298-302. Epub 2005 Sep 23.Binding of amine-substituted N1-benzenesulfonylindoles at human 5-HT6 serotonin receptors.
REF 9Bioorg Med Chem Lett. 2005 Apr 15;15(8):1987-91.Binding of isotryptamines and indenes at h5-HT6 serotonin receptors.
REF 10J Med Chem. 2006 Aug 24;49(17):5217-25.Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors.
REF 11J Med Chem. 2005 Mar 24;48(6):1781-95.Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands.
REF 12Bioorg Med Chem Lett. 2006 Jul 15;16(14):3793-6. Epub 2006 May 18.Binding of methoxy-substituted N1-benzenesulfonylindole analogs at human 5-HT6 serotonin receptors.
REF 13Bioorg Med Chem Lett. 2004 Sep 6;14(17):4569-73.Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors.
REF 14Bioorg Med Chem Lett. 2005 Oct 1;15(19):4230-4.2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists.
REF 15J Med Chem. 2009 Oct 8;52(19):6153-7.Identification of novel indanylsulfonamide guanylhydrazones as potent 5-HT6 serotonin receptor antagonists.
REF 16Bioorg Med Chem Lett. 2010 Mar 1;20(5):1657-60. Epub 2010 Jan 21.3-(Arylsulfonyl)-1-(azacyclyl)-1H-indoles are 5-HT(6) receptor modulators.
REF 17J Med Chem. 2003 Jul 3;46(14):2795-812.Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7).
REF 18J Med Chem. 2007 Nov 15;50(23):5535-8. Epub 2007 Oct 19.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.
REF 19Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. Epub 2009 Nov 20.Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.
REF 20Bioorg Med Chem Lett. 2008 Jan 15;18(2):738-43. Epub 2007 Nov 17.Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists.
REF 21Bioorg Med Chem Lett. 2005 Mar 15;15(6):1707-11.1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands.
REF 22Bioorg Med Chem Lett. 2007 Mar 15;17(6):1691-4. Epub 2007 Jan 4.Further studies on the binding of N1-substituted tryptamines at h5-HT6 receptors.
REF 23Eur J Med Chem. 2010 Feb;45(2):782-9. Epub 2009 Oct 31.8-Sulfonyl-substituted tetrahydro-1H-pyrido[4,3-b]indoles as 5-HT6 receptor antagonists.
REF 24J Med Chem. 2010 Mar 25;53(6):2521-7.5-Cyclic amine-3-arylsulfonylindazoles as novel 5-HT6 receptor antagonists.
REF 255-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. doi: 10.1016/j.nurt.2008.05.008.
REF 26Bioorg Med Chem Lett. 2008 Jan 1;18(1):256-61. Epub 2007 Oct 30.Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation.
REF 27Bioorg Med Chem Lett. 2009 May 1;19(9):2409-12. Epub 2009 Mar 25.Synthesis and SAR of tolylamine 5-HT6 antagonists.
REF 28J Med Chem. 2005 Jan 27;48(2):353-6.Discovery of 5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists.
REF 29Bioorg Med Chem. 2009 Jul 15;17(14):5153-63. Epub 2009 May 29.Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT(6) agonists.
REF 30Bioorg Med Chem Lett. 2005 Jan 17;15(2):379-83.N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor antagonists.
REF 31Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT(6) and 5-HT (2A) receptor mechanisms. Psychopharmacology (Berl). 2010 Jan;208(1):23-36. doi: 10.1007/s00213-009-1702-5. Epub 2009 Oct 23.

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