Abstract

α₁-adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five FDA-approved α₁-AR antagonists (terazosin, doxazosin, alfuzosin, tamsulosin and silodosin) share similar efficacy, they differ in tolerability with reports of ejaculatory dysfunction. The aim of the present work was to revisit their α₁-AR subtype selectivity as well as of LDT5, a compound previously described as a multi-target antagonist of α_1A-/α_1D-AR and 5-HT_1A receptors, and to estimate their affinity for D₂, D₃ and 5-HT_1A receptors, putatively involved in ejaculatory dysfunction. Competition binding assays were performed with native (D₂, 5-HT_1A) or transfected (human α_1A-, α_1B-, α_1Dt-AR and D₃) receptors for determination of drug's affinities. Tamsulosin and silodosin have the highest affinities for α_1A-AR, but only silodosin is clearly a selective α_1A-AR antagonist with Ki ratios of 25.3 and 50.2, for the α_1D-AR and α_1B-AR, respectively. Tamsulosin, silodosin and LDT5, but not terazosin, doxazosin and alfuzosin, have high affinity for the 5-HT_1AR (K_i around 5-10 nM), behaving as antagonists. We conclude that the uroselectivity of tamsulosin is not explained by its too low selectivity for the α_1A- vs. α_1B-AR and that its affinity for D₂ and D₃ receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Present data also support the design of »better-than-LDT5» new multi-target lead compounds with pharmacokinetics selectivity based on poor brain penetration and that could prevent hyperplastic cell proliferation and BPH progression.