Levobetaxolol (Betaxon(TM)) and other beta-adrenergic antagonists: Preclinical pharmacology, IOP-lowering activity and sites of action in human eyes

The pharmacological characteristics of levobetaxolol, a single active isome r of betaxolol, were determined and compared with activities of other,beta -adrenoceptor antagonists. Levobetaxolol (43-fold)beta (1)-selective) exhib ited a higher affinity at cloned human beta (1) (K-i = 0.76 nM) than at bet a (2) (K-i = 32.6 nM) receptors, while dextrobetaxo1ol was much weaker at b oth receptors. Levobetaxolol potently antagonized functional activities at cloned human beta (1) and beta (2) receptors, and also at guinea pig atrial beta (1), tracheal beta (2) and rat colonic beta (3) receptors (IC50S = 33 .2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times beta (1) -selective (vs beta (2)). Levobetaxolol (K-i = 16.4 nM) was more p otent than dextrobetaxolol (K-i = 2.97 muM) at inhibiting isoproterenol-ind uced cAMP production in human non-pigmented ciliary epithelial cells. Levob unolol and (l)-timolol had high affinities at beta (1) and beta (2) recepto rs but were considerably less beta (1)-selective than levobetaxolol. Levo-, dextro- and racemic-betaxolol exhibited little or no affinity, except at s igma sites and Ca2+-channels (IC(50)s > 1 muM), at 89 other receptor/ligand binding sites. Levobetaxolol exhibited a micromolar affinity for L-type Ca 2+-channels. In conscious ocular hypertensive cynomolgus monkeys, levobetax olol was more potent than dextrobetaxo1ol, reducing intraocular pressure by 25.9 +/- 3.2% at a dose of 150 mug/eye (n = 15-30). Quantitative [H-3]-lev obetaxolol autoradiography revealed high levels of binding to human ciliary processes, iris, choroid/retina, and ciliary muscles. In conclusion, levob etaxolol is a potent, high affinity and beta (1)-selective IOP-lowering bet a -adrenoceptor antagonist.