title: Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists.
abstract: The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT(2A) receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major determinant of its 5-HT affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N(1)-substituent, are important factors in controlling binding at 5-HT(2A), 5-HT(2C), 5-HT(1A), and dopamine D2 receptors. Replacement of the N(1)-phenyl ring of spiperone with a methyl group (KML-010; 48) resulted in a compound that binds at 5-HT(2A) receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki >10,000 nM) for 5-HT(2C) and 5-HT(1A) receptors and binds with 400-fold reduced affinity at D2 receptors.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. glennon@hsc.vcu.edu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.forename: Kamel
authors.initials: K
authors.lastname: Metwally
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Dukat
authors.forename: Abd M
authors.initials: AM
authors.lastname: Ismaiel
authors.forename: Joseph
authors.initials: J
authors.lastname: De los Angeles
authors.forename: Jeffery
authors.initials: J
authors.lastname: Herndon
authors.forename: Milt
authors.initials: M
authors.lastname: Teitler
authors.forename: Nantaka
authors.initials: N
authors.lastname: Khorana
mesh_terms: D000818:Animals; D015195:Drug Design; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D007650:Ketanserin / Q000031:analogs & derivatives* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013134:Spiperone / Q000031:analogs & derivatives* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013134:Spiperone; D007650:Ketanserin