- N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists.
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N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.
- Tsai,Dukat,Slassi,MacLean,Demchyshyn,Savage,Roth,Hufesein,Lee,Glennon
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The invention provides a method of treatment or prophylaxis of obesity or for the reduction of food intake, comprising administering to a patient in need of such treatment a therapeutically effective amount of an indole or indoline derivative of Formula I, II or III: wherein the substituents are as described in the specification.
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- N-arylsulfonylindole derivatives as serotonin 5-HT6 receptor ligands
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A series of N1-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT6 receptor with the 5-methoxy-1-benzenesulfonyl analogue (19) having the highest affinity. Additionally, it was discovered that a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl in the 2-position of the indole ring (43) can replace the arylsulfonyl substituent in the 1-position with no loss of affinity. This suggested that the binding conformation of the aminoethyl side chain at this receptor was toward the 4-position of the indole ring and was supported by the fact that the 4-(aminoethyl)indoles (45) also displayed high affinity, as did the conformationally rigid 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19, 43, and 45 all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity over other serotonin receptors tested, with 49 also showing excellent selectivity over all dopamine receptors. In a functional adenylate cyclase stimulation assay, 19 and 49 had no agonist activity, whereas 45 behaved as a partial agonist. Finally, it was shown that 19 had good activity in the 5-HT2A centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.
- Russell,Baker,Barden,Beer,Bristow,Broughton,Knowles,McAllister,Patel,Castro
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p. 3881 - 3895
(2007/10/03)
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- Indole and indoline derivatives as 5-HT6 selective ligands
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Three classes of indole and indoline derivatives are disclosed as ligands selective for the 5-HT6receptors, and hence of value in the treatment or prevention of CNS disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, depression and anxiety. A particular class, 1-substituted-4-(ω-N,N-dialkyl-aminoalkyl)indoles, are claimed as novel compounds.
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- 2-Substituted tryptamines: Agents with selectivity for 5-HT6 serotonin receptors
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Several 2-alkyl-5-methoxytryptamine analogues were designed and prepared as potential 5-HT6 serotonin agonists. It was found that 5-HT6 receptors accommodate small alkyl substituents at the indole 2-position and that the resulting co
- Glennon, Richard A.,Lee, Mase,Rangisetty, Jagadeesh B.,Dukat, Malgorzata,Roth, Bryan L.,Savage, Jason E.,McBride, Ace,Rauser, Laura,Hufeisen, Sandy,Lee, David K. H.
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p. 1011 - 1018
(2007/10/03)
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