Jpn. J. Pharmacol. 87 (3), 189-194 (2001)

Assessment of Affinity and Dissociation Ability of a Newly Synthesized 5-HT₂ Antagonist, AT-1015: Comparison With Other 5-HT₂ Antagonists

Mamunur Rashid¹, Masatomo Watanabe², Mikio Nakazawa³, Takashi Nakamura¹, Kaoru Hattori¹ and Takafumi Nagatomo^1,*

¹Department of Pharmacology, Niigata College of Pharmacy, 5-13-2 Kamishinei-cho, Niigata 950-2081, Japan
²Department of Public Health, Niigata College of Medical Technology, 5-13-2 Kamishinei-cho, Niigata 950-2081, Japan
³Department of Medical Technology, School of Health Sciences, Faculty of Medicine, Niigata University, Niigata 951-8518, Japan

*Corresponding author. FAX: +81-25-268-1280, E-mail: nagatomo@niigata-pharm.ac.jp

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 pK_i 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.

Keywords: AT-1015, 5-HT₂-receptor antagonist, Cerebral cortex (rabbit)

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