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

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.