Binding Affinities of Ocular Hypotensive β -Blockers Levobetaxolol,Levobunolol,and Timolol at Endogenous Guinea Pig β -Adrenoceptors

Abstract

The current study determined the relative affinities and selectivities of numerous β-adrenoceptor antagonists at the endogenous β₁- and β₂-adrenoceptors in guinea pig heart and lung, respectively, using [³H]-CGP12177. Specific binding of [³H]-CGP12177 comprised 80 ± 0.2% (n = 11) and 94 ± 0.2% (n = 16) of the total binding in washed heart and lung homogenates, respectively. Concentration-dependent displacement of [³H]-CGP12177 binding from β-adrenoceptors in both preparations was observed with nine different β-adrenoceptor antagonists. Levobetaxolol, betaxolol, CGP-20712A, levobunolol, and timolol yielded bi-phasic (two-site-fit) competition curves in the heart, while CGP-20712A, ICI-118551 and levobunolol produced bi-phasic curves in the lung preparation. The high-affinity component of [³H]-CGP12177 binding in the heart and lung reflected binding to β₁-receptors and β₂-receptors, respectively. The binding inhibition parameters (IC₅₀s) for displacement of [³H]-CGP12177 from these predominantly high-affinity sites were: levobetaxolol (24.9 ± 1.6 nM heart, 4810 ± 367 nM lung), racemic betaxolol (37.9 ± 8.7 mM heart; 8840 ± 424 mM lung), CGP-20712A (4.6 ± 0.9 nM heart; 171,000 ± 109,000 nM lung), ICI-118551 (9230 ± 3240 nM heart; 2.9 ± 0.6 nM lung), levobunolol (42 ± 15 nM heart, 0.3 ± 0.2 nM lung), (l)-timolol (3.1 nM heart, 2.9 ± 1.5 nM lung), ICI-215001 (5840 ± 114 nM heart; 26100 ± 3200 nM lung), BRL-37344 (83,300 ± 2660 nM heart; 13,200 ± 1250 lung). These data indicated that while levobetaxolol and betaxolol possessed a 193-233-fold selectivity for β₁-receptors, levobunolol exhibited a 140-fold β₂-receptor selectivity and (l)-timolol was essentially nonselective.