title: Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444.
abstract: We examined the pharmacology of (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride (R-96544), the active form of a novel 5-HT(2A) receptor antagonist, (2R,4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride (R-102444). R-96544 produced a concentration-dependent inhibition of platelet aggregation induced by serotonin (5-hydroxytryptamine, 5-HT) alone or in combination with ADP in platelets from humans, monkeys, cats, rabbits, rats and mice. An intravenous administration of R-96544 to rabbits significantly inhibited ex vivo platelet aggregation induced by 5-hydroxytryptamine (5-HT) combined with epinephrine. An oral administration of R-102444 to rats also resulted in significant inhibition of ex vivo platelet aggregation, whereas R-102444 was ineffective in an in vitro platelet aggregation assay. These antiplatelet effects of R-96544 and R-102444 were more potent than those of two other 5-HT(2A) receptor antagonists, sarpogrelate and its active metabolite (+/-)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol hydrochloride (M-1). A binding study using cat platelet membranes showed that R-96544 has high affinity for 5-HT(2A) receptors but no effect on non-serotonergic [3H]ketanserin-binding sites. R-96544 caused a parallel shift to the right of concentration-response curves for 5-HT in rat caudal artery contraction mediated by 5-HT(2A) receptors. Schild plot analysis gave a pA(2) value of 10.4 with a slope near unity (1.04). R-96544 also inhibited 5-HT(2A) receptor-mediated contraction of guinea pig trachea but not 5-HT(3) receptor-mediated contraction of guinea pig ileum and 5-HT(2B) receptor-mediated contraction of rat fundus preparation. R-96544 (i.v.) attenuated the pressor responses evoked by 5-HT (15 microg/kg, i.v.) but not by phenylephrine (5 microg/kg, i.v.) and angiotensin II (0.1 microg/kg, i.v.), after ganglionic blockade in anesthetized spontaneously hypertensive rats. These results show that R-96544, the active form of R-102444, is a novel 5-HT receptor antagonist with potent, competitive, and 5-HT(2A)-selective activity.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Company Limited, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
mesh_terms: D000328:Adult; D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007650:Ketanserin / Q000378:metabolism / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity
chemical_list: C476157:(2R,4R)-4-hydroxy-2-(2-(2-(2-(3-methoxy)phenyl)ethyl)phenoxy)ethyl-1-methylpyrrolidine hydrochloride; D010975:Platelet Aggregation Inhibitors; D011759:Pyrrolidines; C421542:R-102444; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin