Structural Variants of Verapamil and W-7 with Combined Ca2+ Entry Blockade/Myosin Phosphorylation Inhibitory Mechanisms

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Abstract
Arylalkylsulfonamides, identified as Wy-46,622 and Wy-47,324, combine pharmacological properties of the Ca2+ entry blocker verapamil and the calmodulin antagonist W-7. These agents directly inhibit arterial actin-myosin interactions via inhibition of myosin light chain (MLC) phosphorylation in actomyosin. Potencies of both Wy-46,622 (IC50 = 26 .mu.M) and Wy-47,324 (IC50 = 18 .mu.M) are greater than W-7 (IC50 = 35 .mu.M); verapamil is inactive at 100 .mu.M. Both Wy-46,622 and Wy-47,324 are less potent than verapamil, but more potent than W-7, at inhibiting K+-depolarized force development in paced rabbit atria. At higher concentrations (30 .mu.M) which inhibit MLC phosphorylation, Wy-46,622 and Wy-47,324 are either equal to or more efficacious than verapamil in inhibiting receptor-mediated contractions in intact porcine coronary (histamine, serotonin, prostaglandin F2.alpha., carbocyclic thromboxane A2) or guinea pig aortic (leukotriene C4) smooth muscle. Both Wy-47,324 (IC50 = 16 .mu.M) and Wy-46,622 (IC50 = 23 .mu.M) are inhibitors of the second phase of epinephrine-induced human platelet aggregation; Wy-47,324 is more potent than verapamil or W-7 (IC50 for each = 29 .mu.M). These results suggest that these agents possess combined Ca2+ entry blocker/MLC phosphorylation inhibitory mechanisms. Furthermore, they are more vascular specific than verapamil, and are effective inhibitors of intracellular Ca2+-mediated events in vascular smooth muscle and platelets.