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

The new antiplatelet agent sarpogrelate (MCI-9042), its major metaboli te (R,S)-1-[2-[2-(3 methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-p ((R,S)-M-1) and the enantiomers of(R,S)-M-1 were studied as antagonis ts at 5-HT2A receptors, 5-HT1-like receptors, 5-HT3 receptors, alpha(1 )-adrenoceptors, beta adrenoceptors, histamine H-1 receptors, histamin e H-2 receptors and muscarinic M(3) receptors in various functional in -vitro assays. Sarpogrelate, (R,S)-M-1, (R)-M-1 and (S)-M-1, respectiv ely, were competitive antagonists of 5-hydroxytryptamine (5-HT) at 5-H T2A receptors of rat tail artery with calculated pA(2) values of 8.53, 9.04, 9.00 and 8.81, respectively. Sarpogrelate lacked prominent 5-HT 1-like, 5-HT3, beta, H-1, H-2 and M(3) antagonist activity and weakly blocked alpha(1)-adrenoceptors (pK(B) = 6.80). (S)-M-1 showed weak aff inity for 5-HT1-like receptors (pK(B) = 6.30), alpha(1)- (pK(B) = 6.80 ) and beta- (pK(B) = 6.54) adrenoceptors, while (R)-M-1 was a weak ant agonist at histamine H-1 receptors (pK(B) = 649). Stereoselectivity of M-1 enantiomers was low. (R)-M-1 showed 1.6-fold, 2.3-fold and 2.5-fo ld higher antagonist activity than (S)-M-1 for 5-HT2A, H-1 and M(3) re ceptor, respectively. Affinity at beta-adrenoceptors and 5-HT1-like re ceptors 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 mu M) 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)- a nd (S)-M-1 failed to differ in restoring the ritanserin-induced depres sion of the 5-HT maximum response. It is concluded that sarpogrelate, its major metabolite (R,S)-M-1, and M-1 enantiomers are specific antag onists of 5-HT at 5-HT2A receptors. The stereochemical configuration o f the ligands does not seem to be crucial for binding to the 5-HT2A re ceptor. Like ketanserin, sarpogrelate and M-1 enantiomers appear to be allosteric activators of the 5-HT2A receptor system in rat tail arter y.