McN-5691: a novel vasodilator which blocks receptor-operated and potential-dependent calcium channels in rabbit aorta

The mechanism of action of the novel vasodilator McN-5691 (N-(2-(3,4-dimethoxyphenyl)ethyl)-5-methoxy-N,..cap alpha..-dimethyl-2-(phenylethynyl)benzenepropanamine HCl) (McN) was studied in rabbit thoracic aortic rings. The effects of McN (0.1-10..mu..M) to inhibit the KCl-sensitive potential-dependent calcium (Ca) channel (PDC) and the norepinephrine (NE) sensitive receptor-operated Ca channel (ROC) were evaluated by measuring McN's effects on the active development of isometric tension and on the activation of Ca influx (/sup 45/Ca)(CI) through both channels as well as leak channel CI. McN had no effect on the leak channel but blocked PDC and ROC CI (1,10..mu..M) and active tension development (KCl: 1,10..mu..M; NE: 10..mu..M). McN also relaxed rings precontracted with NE (1..mu..M) and KCl (30mM) with similar potency (IC/sub 50/ against NE = 159..mu..M; KCl = 190..mu..M). McN did not inhibit intracellular Ca release or Ca-calmodulin interaction as evidenced by a lack of effect on NE-induced isometric tension development in zero Ca buffer. McN did not enhance Ca efflux from unstimulated or from NE-stimulated rings preloaded with /sup 45/Ca. Receptor binding studies using membrane preparations from rat cerebral cortex showed little or no ..cap alpha..-1 (/sup 3/H-WB4101) antagonist activity and no binding to the ..cap alpha..-2 (/sup 3/H-clonidine) receptor. These results indicate that McN is a novelmore » dual-channel Ca blocker vasodilator which lacks intracellular effects.« less