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: L R Bush, D C Remy
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 247 Issue 2 Pg. 796-802 (Nov 1988) ISSN: 0022-3565 [Print] United States
• PMID: 3183974 (Publication Type: Journal Article)

Chemical References

• Cyproheptadine
• Serotonin
• Adenosine Diphosphate
• 3-methoxycyproheptadine

Topics

• Adenosine Diphosphate (pharmacology)
• Animals
• Coronary Circulation (drug effects)
• Coronary Disease (physiopathology)
• Coronary Thrombosis (physiopathology)
• Cyproheptadine (analogs & derivatives, pharmacology)
• Dogs
• Female
• Hemodynamics (drug effects)
• Isomerism
• Male
• Platelet Aggregation (drug effects)
• Serotonin (pharmacology)
• Vasoconstriction (drug effects)