Assessment of Affinity and Dissociation Ability of a Newly Synthesized 5-HT_2 Antagonist, AT-1015: Comparison With Other 5-HT_2 Antagonists

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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 ≅ AT-1015 > cyproheptadine ≅ 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.
社団法人日本薬理学会の論文
2001-11-01

Assessment of Affinity and Dissociation Ability of a Newly Synthesized 5-HT_2 Antagonist, AT-1015: Comparison With Other 5-HT_2 Antagonists

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