Lipid solubility of vasodilatory vanilloid-type β-blockers on the functional and binding activities of β-adrenoceptor subtypes

Various vanilloid-type β-adrenoceptor blockers were studied on guinea pig right atrium and trachea and rat colon. In addition, we also investigated their β₁-, β₂-, and β₃-adrenoceptor binding affinities. All these β-adrenergic antagonists inhibited (−)isoproterenol-induced positive chronotropic effects of the right atrium and tracheal relaxation responses in a concentration-dependent manner. Some of these agents prevented the inhibition of rat colon spontaneous motility by (−)isoproterenol. Of the agents tested, we found that ferulidilol, eugenodilol, eugenolol, isoeugenolol, and ferulinolol, as well as propranolol and metoprolol, possessed β₃-adrenoceptor blocking activities, others were nearly without effectiveness. Furthermore, the binding characteristics of vanilloid-type β-adrenergic antagonists were evaluated in [³H]CGP-12177, a β₁/β₂-adrenoceptor blocker and a β₃-adrenoceptor agonist, binding to β₁-, β₂-, and β₃-adrenoceptor sites in rat ventricle, lung, and interscapular brown adipose tissue (IBAT) membranes, respectively. Eugenodilol, eugenolol, metoprolol, isoeugenolol, and ferulinolol were less potent than both propranolol and ferulidilol in competing for the β₃-adrenoceptor binding sites. From the results of in vitro functional and binding studies, we suggested that propranolol, ferulidilol, eugenodilol, eugenolol, metoprolol, isoeugenolol, and ferulinolol all possessed β₃-adrenoceptor blocking activities. On the other hand, we also found that eugenodilol, eugenolol, metoprolol, isoeugenolol, and ferulinolol had a low lipid solubility in comparison with propranolol and ferulidilol. In conclusion, we proposed that β₃-adrenoceptor antagonistic actions of these vanilloid-type β-blockers were positively correlated with their lipid solubility.