The pharmacologic profile of a
cyproheptadine-related compound, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]
piperidine hydrochloride (AH-1058), was assessed in various in vivo and in vitro models. In guinea pig cardiomyocytes,
AH-1058 effectively suppressed L-type Ca2+ channel currents without affecting other
ion channel or ion exchange currents. In rat cerebral cortical membranes
AH-1058 appears to bind preferentially to L-type Ca2+ channels at phenylalkylamine- and benzothiazepine-binding sites. In canine isolated, blood-perfused heart preparations,
AH-1058 exerted negative inotropic, dromotropic, and chronotropic and weak coronary
vasodilator effects. In
halothane-anesthetized dogs,
AH-1058 suppressed ventricular contractility and decreased blood pressure and cardiac output. Total peripheral vascular resistance was hardly affected by the
drug, suggesting that in vivo
AH-1058 can selectively suppress cardiac, as compared to peripheral vascular, function. In conscious dogs, by
intravenous administration AH-1058 reduced systolic blood pressure and maximal upstroke velocity of the left ventricular pressure, while it increased heart rate in a dose-dependent manner. The
drug did not affect diastolic blood pressure, which is quite different from cardiovascular properties of well-known Ca2+ channel blockers,
verapamil and
diltiazem. This unique cardiovascular profile of
AH-1058 is expected to be useful in the treatment of certain
pathological processes such as the obstructive
hypertrophic cardiomyopathy,
vasovagal syncope, dissecting
aortic aneurysm, and ventricular arrhythmias, in which selective inhibition of the ventricular Ca2+ channels is essential for
drug therapy.