In-vitro Pharmacology of Sarpogrelate and the Enantiomers of its Major Metabolite: 5-HT2A Receptor Specificity, Stereoselectivity and Modulation of Ritanserin-induced Depression of 5-HT Contractions in Rat Tail Artery

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Abstract
The new antiplatelet agent sarpogrelate (MCI-9042), its major metabolite (R,S)-1-[2-[2-(3-methoxyphe-nyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol ((R,S)-M-1) and the enantiomers of (R,S)-M-1 were studied as antagonists at 5-HT2A receptors, 5-HT1-like receptors, 5-HT3 receptors, α1-adrenoceptors, β-adrenoceptors, histamine H1 receptors, histamine H2 receptors and muscarinic M3 receptors in various functional in-vitro assays. Sarpogrelate, (R,S)-M-1, (S)-M-1 and (S)-M-1, respectively, were competitive antagonists of 5-hydroxytryptamine (5-HT) at 5-HT2A receptors of rat tail artery with calculated pA2 values of 8·53, 9·04, 9·00 and 8·81, respectively. Sarpogrelate lacked prominent 5-HTt like, 5-HT3, β, Ht, H2 and M3 antagonist activity and weakly blocked α1-adrenoceptors (pKB = 6·30). (S)-M-1 showed weak affinity for 5-HT1-like receptors (pKB = 6·30), α1 (pKB = 6·80) and β (pKB = 6·54) adrenoceptors, while (R)-M-1 was a weak antagonist at histamine H1 receptors (pKB = 6·49). Stereoselectivity of M-1 enantiomers was low. (R)-M-1 showed 1·6-fold, 2·3-fold and 2·5-fold higher antagonist activity than (S)-M-1 for 5-HT2A, H1 and M3 receptor, respectively. Affinity at β-adrenoceptors and 5-HT1-like receptors was 5-fold and 3-fold higher for (S)-M-1 than for (R)-M-1. The depression of the maximum effect of 5-HT-induced contractions of rat-tail artery which amounted to 58–72% in the presence of ritanserin (1 nm), was totally prevented after preincubation with sarpogrelate (1 μm) and (R)- and (S)-M-1 (30 and 300 nm), respectively, and partially prevented after preincubation with (R)- and (S)-M-1 (0·3-3 nm). (R)- and (S)-M-1 failed to differ in restoring the ritanserin-induced depression of the 5-HT maximum response. It is concluded that sarpogrelate, its major metabolite (R, S)-M-1 and M-1 enantiomers are specific antagonists of 5-HT at 5-HT2A receptors. The stereochemical configuration of the ligands does not seem to be crucial for binding to the 5-HT2A receptor. Like ketanserin, sarpogrelate and M-1 enantiomers appear to be allosteric activators of the 5-HT2A receptor system in rat tail artery.

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