Eugenodilol: A third-generation beta-adrenoceptor blocker, derived from eugenol, with alpha-adrenoceptor blocking and beta(2)-adrenoceptor agonist-associated vasorelaxant activities

Eugenodilol, derived from natural eugenol, was first investigated with in v ivo and in vitro models. In our in vivo study, eugenodilol (0.5, 1.0, and 1 .5 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardic respons es in pentobarbital-anesthetized Wistar rats. Eugenodilol also inhibited th e tachycardia and arterial pressor effects induced by (-)isoproterenol and phenylephrine, respectively. In our in vitro study, eugenodilol competitive ly antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects and tracheal-relaxation responses on isolated guinea pig tissues i n a concentration-dependent manner. The apparent pA(2) values were 7.88 +/- 0.12 for right atria, 7.52 +/- 0.05 for left atria and 7.33 +/- 0.15 for t rachea, indicating that eugenodilol was a nonselective beta-adrenoceptor bl ocker. In thoracic aorta experiments, the apparent pA(2) values of alpha-ad renoceptor blockade were 7.05 +/- 0.25 and 6.87 +/- 0.08 for eugenodilol an d labetalol, respectively. In addition, eugenodilol produced cumulative rel axation responses on isolated guinea pig tracheal strips. The effects were competitively antagonized by ICI 118,551 (10(-8)-10(-6) M), a relatively se lective beta(2)-adrenoceptor antagonist. Zn the radioligand-binding assay, the K-i values of [H-3]CGP-12177 binding to rat ventricle and lung membrane s were 9.72 and 48.29 nM, respectively, and the value of [H-3]prazosin bind ing to rat brain membrane was 38.72 nM. These results further confirmed the alpha/beta-odronoceptors-blocking activities of eugenodilol reported in th e functional studies. We conclude that eugenodilol is a novel third-generat ion P-adrenoceptor blocker with ancillary blocking activity at alpha-adreno ceptors and weak sympathomimetic activity at beta(2)-adrenoceptors.