PHARMACOLOGY OF TAMSULOSIN - SATURATION-BINDING ISOTHERMS AND COMPETITION ANALYSIS USING CLONED ALPHA(1)-ADRENERGIC RECEPTOR SUBTYPES

BACKGROUND. alpha(1)-adrenergic receptors (alpha(1) ARs) are important in the dynamic component of benign prostatic hyperplasia (BPH). Curre ntly, several (alpha(1) AR antagonists are being used in the treatment of BPH. METHODS. In order to more fully characterize the pharmacology of the alpha(1) AR antagonist tamsulosin, we utilized saturation-bind ing isotherms with [H-3] tamsulosin to determine the Kd of this compou nd at all three cloned (alpha(1) AR subtypes stably expressed in rat-1 fibroblasts. To confirm these results, we performed competition bindi ng experiments, displacing [I-125]HEAT With increasing concentrations of alfuzosin, doxazosin, 5-methyl-urapidil, prazosin, tamsulosin, tera zosin, and (+)YM617 (stereoisomer of tamsulosin) in the same clonal ce ll lines. RESULTS. [H-3] tamsulosin binds to cloned (alpha(1) AR subty pes with a rank order of affinity of alpha(1a) = alpha(1d) > alpha(1b) . Competition experiments confirmed the relative nonselectivity of alf uzosin, doxazosin, and prazosin, but revealed slight alpha(1b) = alpha (1d) > alpha(1a) selectivity for terazosin, and clear alpha(1a) = alph a(1d) > alpha(1b) for (+)YM617 and tamsulosin([-]YM617); alpha(1a) > a lpha(1d) > alpha(1b) selectivity for 5-methyl-urapidil was confirmed. CONCLUSIONS. We conclude that tamsulosin displays selectivity for alph a(1a) and alpha(1d) ARs. This selectivity may contribute to the tamsul osin efficacy reported in several recent clinical studies in patients with BPH. (C) 1997 Wiley-Liss, Inc.