title: Assessment of affinity and dissociation ability of a newly synthesized 5-HT2 antagonist, AT-1015: comparison with other 5-HT2 antagonists.
abstract: This study investigated the binding affinities of a newly synthesized 5-HT2 antagonist, AT-1015 (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate) for [3H]ketanserin bindings to 5-HT2 receptors in the rabbit cerebral cortex membranes using the radioligand binding assay method. The affinity of this compound was also compared with other 5-HT2-selective antagonists such as ketanserin, sarpogrelate, cyproheptadine and ritanserin, and the results showed that AT-1015 has a high pKi value for the 5-HT2 receptor. The rank order of these antagonists are: ritanserin > ketanserin approximately equal to AT-1015 > cyproheptadine approximately equal to sarpogrelate. We also evaluated the dissociation ability (slow or rapid) of AT-1015 in the rabbit cerebral cortex membrane and compared it with other 5-HT2 antagonists using the radioligand binding assay method. The blockade of [3H]ketanserin binding sites in the rabbit cerebral cortex induced by ketanserin and sarpogrelate was readily reversed by washing, whereas the inhibition by AT-1015, cyproheptadine and ritanserin was not readily reversed by washing. The % of control after washing are 76.10% and 49.55% for AT-1015 at 10(-7.5) and 10(-7.0) M, 67.32% and 50.17% for cyproheptadine at 10(7.5) and 10(-7.0) M, and 72.38% and 39.80% for ritanserin at 10(-9.5) and 10(-9.0) M concentrations, respectively. Thus, these findings suggest that AT-1015 has antagonistic properties towards the 5-HT2 receptor and also shows that AT-1015 slowly dissociates from the 5-HT2 receptor, whereas, ketanserin and sarpogrelate dissociate rapidly from the 5-HT2 receptor, which do not correlate with their affinity.
authors.affiliation: Department of Pharmacology, Niigata College of Pharmacy, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Rashid
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Nakazawa
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Hattori
authors.forename: T
authors.initials: T
authors.lastname: Nagatom
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D007540:Isonipecotic Acids; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D007540:Isonipecotic Acids; C411870:N-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-yliden)piperidino)ethyl)-1-formyl-4-piperidinecarboxamide; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin