title: 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.
abstract: The new antiplatelet agent sarpogrelate (MCI-9042), its major metabolite (R,S)-1-[2-[2-(3-methoxyphenyl)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, alpha 1-adrenoceptors, beta-adrenoceptors, histamine H1 receptors, histamine H2 receptors and muscarinic M3 receptors in various functional in-vitro assays. Sarpogrelate, (R,S)-M-1, (R)-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-HT1-like, 5-HT3, beta, H1, H2 and M3 antagonist activity and weakly blocked alpha 1-adrenoceptors (pKB = 6.30). (S)-M-1 showed weak affinity for 5-HT1-like receptors (pKB = 6.30), alpha 1- (pKB = 6.80) and beta- (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 beta-adrenoceptors and 5-HT1-like receptors was 5-fold and 3-fold higher for (S)-M-1 than for (R)-M-1.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Fachbereich Pharmazie, Freie Universität Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Pertz
authors.forename: S
authors.initials: S
authors.lastname: Elz
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D016713:Ritanserin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013237:Stereoisomerism; D013386:Succinates / Q000494:pharmacology*; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013386:Succinates; D016713:Ritanserin; C064294:sarpogrelate