Abstract

α₁-Adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five Food and Drug Administration–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 (1-(2-methoxyphenyl)-4-[2-(3,4-dimethoxyphenyl) ethyl]piperazine monohydrochloride), a compound previously described as a multitarget 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, which are 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 the 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 K_i ratios of 25.3 and 50.2 for the α_1D- and α_1B-AR, respectively. Tamsulosin, silodosin, and LDT5 (but not terazosin, doxazosin, and alfuzosin) have high affinity for the 5-HT_1A receptor (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- versus 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 multitarget lead compounds with pharmacokinetic selectivity based on poor brain penetration and that could prevent hyperplastic cell proliferation and BPH progression.