MODULATION OF PLATELET-FUNCTION AND VASCULAR SMOOTH-MUSCLE CONTRACTILE ACTIONS BY A NOVEL, SELECTIVE, HIGHLY POTENT 5-HT2 ANTAGONIST (SR46349)

SR46349 is a novel, selective 5-HT2 receptor antagonist with the chemi cal structure (trans, 4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3(2-flu rophenyl) propen-1-yl]phenol hemifumarate). This agent has been found to exhibit antithrombotic actions in animal models of thrombosis. In o rder to investigate the effects of this agent on agonist induced vascu lar smooth muscle contraction, we utilized rabbit aortic ring and rat aortic strip preparations. Serotonin and platelet rich plasma (PRP) ac tivated with arachidonic acid (AA) were used to determine the modulato ry effect of SR46349. The IC50 for SR46349 was found to be: 1) rabbit aortic ring: 0.4 +/- 0.1 ng/ml for 5-HT and 0.25 +/- 0.05 ng/ml for PR P/AA. 2) rat aortic strip: 0.5 +/- 0.1 ng/ml for 5-HT and 0.3 +/- 0.1 ng/ml for PRP/AA. These results indicate that SR46349 is a highly pote nt inhibitor of aortic smooth muscle contraction. To further study the structure-activity relationship, we utilized the cis derivative of th is agent, SR46615. This agent was found to be a relatively weaker inhi bitor of the agonist induced aortic smooth muscle contraction. The stu dies reported here provide also comparative data on ketanserin, ritans erin and two new serotonin antagonists on the smooth muscle modulatory actions.