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

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Abstract
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 (Ki = 0.76 nM) than at β2 (Ki = 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 β3 receptors (IC50s = 33.2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times β1-selective (vsβ2). Levobetaxolol (Ki = 16.4 nM) was more potent than dextrobetaxolol (Ki = 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.