Assessment of affinity and dissociation ability of a newly synthesized 5-HT2 antagonist, AT-1015: comparison with other 5-HT2 antagonists.

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.