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 chemical structure (trans, 4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3(2-flurophenyl) propen-1-yl]phenol hemifumarate). This agent has been found to exhibit antithrombotic actions in animal models of thrombosis. In order to investigate the effects of this agent on agonist induced vascular smooth muscle contraction, we utilized rabbit aortic ring and rat aortic strip preparations. Serotonin and platelet rich plasma (PRP) activated with arachidonic acid (AA) were used to determine the modulatory 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 PRP/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 potent inhibitor of aortic smooth muscle contraction. To further study the structure-activity relationship, we utilized the cis derivative of this agent, SR46615. This agent was found to be a relatively weaker inhibitor of the agonist induced aortic smooth muscle contraction. The studies reported here provide also comparative data on ketanserin, ritanserin and two new serotonin antagonists on the smooth muscle modulatory actions.