title: Effects of 3-methoxycyproheptadine in a canine model of coronary thrombosis.
abstract: The enantiomers of 3-methoxycyproheptadine (3-MeO-Cyp) were evaluated for their ability to abolish cyclic flow reductions (CFRs) in stenosed and partially de-endothelialized coronary arteries of open chest dogs. These enantiomers demonstrate differential serotonin antagonism with the levorotatory (-) enantiomer showing a selective antiserotonin profile. (+)- and (-)-3-MeO-Cyp each were evaluated in 5 dogs, at doses ranging from 0.01 to 0.5 mg/kg i.v. 1 hr after establishing CFRs, which were quantified in terms of frequency (CFR/hour) and severity (average nadir of coronary blood flow). The frequency or severity of CFRs was not affected consistently by 10 or 25 micrograms/kg of (-)-3-MeO-Cyp; however, 50 micrograms/kg practically abolished CFRs. (+)-3-MeO-Cyp was significantly less potent; complete abolition of CFRs required 0.5 mg/kg of this enantiomer in three dogs, and partial abolition occurred in the other two. These differences between (+)- and (-)-3-MeO-Cyp correlated well with a 12-fold difference in potency for inhibition of canine platelet aggregation stimulated by serotonin and ADP. The IC50's of (-)- and (+)-3-MeO-Cyp vs. ADP plus serotonin-induced aggregation of canine platelet-rich plasma were 1.03 +/- 0.39 (mean +/- S.E.) and 12.92 +/- 4.28 microM, respectively. Thus, (-)-3-MeO-Cyp, a 5-HT2 antagonist devoid of anticholinergic activity and less antihistamine activity than either its enantiomer or parent drug, cyproheptadine, exerts dose-dependent antithrombotic effects in this canine model, providing further evidence that serotonin plays an important role in platelet aggregation and thrombosis.
authors.affiliation: Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
authors.forename: L R
authors.initials: LR
authors.lastname: Bush
authors.forename: D C
authors.initials: DC
authors.lastname: Remy
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology*; D003328:Coronary Thrombosis / Q000503:physiopathology*; D003533:Cyproheptadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007536:Isomerism; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D003533:Cyproheptadine; D012701:Serotonin; D000244:Adenosine Diphosphate; C057719:3-methoxycyproheptadine