Vaninolol: A new selective β₁-adrenoceptor antagonist derived from vanillin

The β-adrenoceptor blocking properties of vaninolol ((±)4-[4'-(2-hydroxy-3-tert-butyl-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 pressor action in urethane-anesthetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. These findings suggested that vaninolol possessed β-adrenergic blocking activity, but was without α-adrenergic blocking activity. In isolated guinea-pig tissues, vaninolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that vaninolol was a β-adrenoceptor competitive antagonist. The effect of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some β₁-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol > vaninolol > propranolol. In addition, vaninolol had a mild direct cardiac depression at high concentrations and was without intrinsic sympathomimetic activity (ISA). Furthermore, binding characteristics of vaninolol and other β-adrenoceptor antagonists were evaluated in [³H]dihydroalprenolol binding to guinea-pig ventricular membranes. The order of potency of β-adrenoceptor antagonists in competing for the binding sites was (-)propranolol > vaninolol ≥ atenolol. In conclusion, vaninolol was found to be a selective β₁-adrenoceptor antagonist with relatively low lipophilicity in comparison with propranolol, devoid of ISA, and had a mild myocardial depressant effect.