title: N-Arylsulfonylindole derivatives as serotonin 5-HT(6) receptor ligands.
abstract: A series of N(1)-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT(6) 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-HT(2A) centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, United Kingdom. michael_russell@merck.com
authors.forename: M G
authors.initials: MG
authors.lastname: Russell
authors.forename: R J
authors.initials: RJ
authors.lastname: Baker
authors.forename: L
authors.initials: L
authors.lastname: Barden
authors.forename: M S
authors.initials: MS
authors.lastname: Beer
authors.forename: L
authors.initials: L
authors.lastname: Bristow
authors.forename: H B
authors.initials: HB
authors.lastname: Broughton
authors.forename: M
authors.initials: M
authors.lastname: Knowles
authors.forename: G
authors.initials: G
authors.lastname: McAllister
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: J L
authors.initials: JL
authors.lastname: Castro
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008635:Mescaline / Q000494:pharmacology; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007211:Indoles; D008024:Ligands; C439955:N,N-dimethyl-2-(1-(benzenesulfonyl)-5-methoxy-1H-indol-3-yl)ethylamine; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D013450:Sulfones; C097216:serotonin 6 receptor; D008635:Mescaline