VANINOLOL - A NEW SELECTIVE BETA(1)-ADRENOCEPTOR ANTAGONIST DERIVED FROM VANILLIN

The beta-adrenoceptor blocking properties of vaninolol yl-aminopropoxy )-3'-methoxyphenyl]-3-buten-2-one), derived from vanillin, were first investigated under in vivo and in vitro conditions. Vaninolol (0.1, 0. 5, 1.0 mg/kg, i.v.), as well as propranolol, produced a dose-dependent bradycardia response and a sustained presser action in urethane-anest hetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arteri al presser responses induced by phenylephrine. These findings suggeste d that vaninolol possessed beta-adrenergic blocking activity, but was without alpha-adrenergic blocking activity. In isolated guinea-pig tis sues, vaninolol antagonized (-)isoproterenol-induced positive inotropi c and chronotropic effects of the atria and tracheal relaxation respon ses in a concentration-dependent manner. The parallel shift to the rig ht of the concentration-response curve of (-)isoproterenol suggested t hat vaninolol was a beta-adrenoceptor competitive antagonist. The effe ct of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some beta(1)-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol much greater than vaninolol > propranolol. In addition, vaninolol had a mild direct card iac depression at high concentrations and was without intrinsic sympat homimetic activity (ISA). Furthermore, binding characteristics of vani nolol and other beta-adrenoceptor antagonists were evaluated in [H-3]d ihydroalprenolol binding to guinea-pig ventricular membranes. The orde r of potency of beta-adrenoceptor antagonists in competing for the bin ding sites was (-)propranolol much greater than vaninolol greater than or equal to atenolol. In conclusion, vaninolol was found to be a sele ctive beta(1)-adrenoceptor antagonist with relatively low lipophilicit y in comparison with propranolol, devoid of ISA, and had a mild myocar dial depressant effect.