title: Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists.
abstract: Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6 receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8-13) appear to be able to adopt a conformation that allows high affinity 5-HT6 receptor binding, while the beta-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. coledc@wyeth.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: William J
authors.initials: WJ
authors.lastname: Lennox
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stock
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Hossein
authors.initials: H
authors.lastname: Mazandarani
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Smith
authors.forename: Guoming
authors.initials: G
authors.lastname: Zhang
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tawa
authors.forename: Lee E
authors.initials: LE
authors.lastname: Schechter
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C097216:serotonin 6 receptor; C030820:tryptamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases