A pharmacological and biochemical examination of AHR-16462B, a novel calcium antagonist coronary vasodilator/antihypertensive

Abstract

A series of pharmacological and biochemical studies were conducted to characterize AHR-16462B 4-[bis(4-fluorophenyl)methyl]-1-(2-naphthalenylmethyl)piperidine (HCI), a novel antagonist of voltage-sensitive calcium channels. AHR-16462B displaced [3H]-nimodipine binding from calcium channels on rabbit skeletal muscle membranes (IC50 = 118 nM) and inhibited depolarization-induced changes in intracellular free calcium in cultured PC-12 cells (IC50 = 125 nM), but had virtually no effects on binding of specific radioligands to 5-HT1a, 5-HT2, alpha1, alpha2, dopamine2, beta1, beta2, muscarinic M1, or histamine H1 receptors. AHR-16462B antagonized CaCI2-induced contractions of depolarized rabbit aortic strips (pA2 = 8.83), but had no negative chronotropic, and only slight negative inotropic effects on isolated guinea pig atria. In anesthetized dogs, cumulative doses of 0.1, 0.4, and 1.4 mg/kg, i. v., AHR-16462B decreased coronary vascular resistance and blood pressure; the magnitude and duration of these effects were dose related. Heart rate and Lead 2 ECG waveforms remained unaltered at all doses. In conscious spontaneously hypertensive rats (SHR), 3 to 100 mg/kg, p. o., AHR-16462B produced marked, long-lasting, and dose-related antihypertensive actions. Heart rate remained unaltered following 3, 10, and 30 mg/kg AHR-16462B, and bradycardia was evoked by 100 mg/kg. Effective antihypertensive doses of AHR-16462B had modest natriuretic and/or chloruretic actions.