Structural variants of verapamil and W-7 with combined Ca2+ entry blockade/myosin phosphorylation inhibitory mechanisms.
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 microM) and Wy-47,324 (IC50 = 18 microM) are greater than W-7 (IC50 = 35 microM); verapamil is inactive at 100 microM. 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 microM) 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 microM) and Wy-46,622 (IC50 = 23 microM) 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 microM). 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.
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002417:Cattle; D004837:Epinephrine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D013449:Sulfonamides; D014665:Vasodilator Agents; C017967:W 7; D000205:Actomyosin; D014700:Verapamil; D009218:Myosins; D004837:Epinephrine