Levobetaxolol (Betaxon™) and Other β -Adrenergic Antagonists: Preclinical Pharmacology,IOP-Lowering Activity and Sites of Action in Human Eyes

The pharmacological characteristics of levobetaxolol, a single active isomer of betaxolol, were determined and compared with activities of other β-adrenoceptor antagonists. Levobetaxolol (43-fold β₁-selective) exhibited a higher affinity at cloned human β₁ (K_i = 0.76 nM) than at β₂ (K_i = 32.6 nM) receptors, while dextrobetaxolol was much weaker at both receptors. Levobetaxolol potently antagonized functional activities at cloned human β₁ and β₂ receptors, and also at guinea pig atrial β₁, tracheal β₂ and rat colonic β ₃ receptors (IC₅₀s = 33.2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times β₁-selective (vs β₂). Levobetaxolol (K_i = 16.4 nM) was more potent than dextrobetaxolol (K_i = 2.97 μM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells. Levobunolol and (l)-timolol had high affinities at β₁ and β₂ receptors but were considerably less β₁-selective than levobetaxolol. Levo-, dextro- and racemic-betaxolol exhibited little or no affinity, except at sigma sites and Ca²⁺-channels (IC₅₀s > 1 μM), at 89 other receptor/ligand binding sites. Levobetaxolol exhibited a micromolar affinity for L-type Ca²⁺-channels. In conscious ocular hypertensive cynomolgus monkeys, levobetaxolol was more potent than dextrobetaxolol, reducing intraocular pressure by 25.9 ± 3.2% at a dose of 150 μg/eye (n = 15–30). Quantitative [³H]levobetaxolol autoradiography revealed high levels of binding to human ciliary processes, iris, choroid/retina, and ciliary muscles. In conclusion, levobetaxolol is a potent, high affinity and β₁-selective IOP-lowering β-adrenoceptor antagonist.