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 [ 3 H]‐nimodipine binding from calcium channels on rabbit skeletal muscle membranes (IC 50 = 118 nM) and inhibited depolarization‐induced changes in intracellular free calcium in cultured PC‐12 cells (IC 50 = 125 nM), but had virtually no effects on binding of specific radioligands to 5‐HT 1a , 5‐HT 2 , alpha 1 , alpha 2 , dopamine 2 , beta 1 , beta 2 , muscarinic M 1 , or histamine H 1 receptors. AHR‐16462B antagonized CaCI 2 ‐induced contractions of depolarized rabbit aortic strips (pA 2 = 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.