LAS 30538 is a novel calcium channel blocker that demonstrates potent vasodilator effects with less myocardial depression than verapamil in preclinical models.
May inform next-generation calcium channel blocker design with reduced cardiodepression; leaves open translation to human hypertension.
A new compound, 1-[2-(2,6-dimethylphenoxy)ethyl]-alpha,alpha-bis-(p-fluorphenyl)-4 -piperidine methanol (LAS 30538), was found to have potent vasodilator effects. Its vasorelaxant activity was demonstrated in rat perfused hindlimbs contracted with 80 mM K+, having an IC50 value of 40 nM. In conscious spontaneously hypertensive rats, LAS 30538 administered orally, caused dose-dependent sustained falls in systolic blood pressure with an ED30 value of 11 mg kg-1. In pithed rats, LAS 30538, strongly inhibited vasoconstriction induced by the alpha 2-adrenoceptor agonist B-HT 933 and the calcium agonist compound Bay K8644 with ED50 values of 4 mg kg-1 p.o. and 1.3 mg kg-1 i.v., respectively. Results from electrophysiological studies carried out using guinea-pig papillary muscles partially depolarized by 22 mM K+ are consistent with LAS 30538 acting as a Ca(2+)-channel blocker. When compared with verapamil, in guinea-pig and rabbit isolated heart preparations, LAS 30538 caused less cardiodepression and bradycardia. The results suggest that LAS 30538 may have some advantages over other Ca(2+)-channel blockers such as verapamil in causing less myocardial depression for a given level of vasodilatation.
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Cardelús et al. (1992) studied this question.
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