title: Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding.
abstract: Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C receptors and even less is known about the influence of its structural features on 5-HT1C receptor affinity. The present study reveals that the fluoro and carbonyl groups of the 4-fluorobenzoyl portion of ketanserin make small contributions to 5-HT2 binding and that the intact benzoylpiperidine moiety is an important feature. Ring-opening of the piperidine ring reduces affinity. Although the quinazoline-2,4-dione moiety also contributes to binding, it appears to play a smaller role and can be structurally simplified with retention of 5-HT2 affinity. N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine (39), for example, binds with nearly the same affinity (Ki = 5.3 nM) as ketanserin (Ki = 3.5 nM). All of the compounds examined bind at 5-HT1C sites with lower affinity than ketanserin, and some of the simplified analogues bind with nearly 10 times the 5-HT2 versus 5-HT1C selectivity of ketanserin; however, none displays > 120-fold selectivity. Several of the compounds, such as the amide 32 and the urea 33 represent examples of new structural classes of 5-HT2 ligands.
authors: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540.
authors: J L
authors: JL
authors: Herndon
authors: A
authors: A
authors: Ismaiel
authors: S P
authors: SP
authors: Ingher
authors: M
authors: M
authors: Teitler
authors: R A
authors: RA
authors: Glennon
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D007650:Ketanserin / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin