PT - JOURNAL ARTICLE AU - Bruna Maria Castro Salomão Quaresma AU - Amanda Reis Pimenta AU - Anne Caroline Santos da Silva AU - André Sampaio Pupo AU - Luiz Antonio S. Romeiro AU - Claudia Lucia Martins Silva AU - François Noël TI - Revisiting the Pharmacodynamic Uroselectivity of <em>α</em><sub>1</sub>-Adrenergic Receptor Antagonists AID - 10.1124/jpet.119.260216 DP - 2019 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 106--112 VI - 371 IP - 1 4099 - http://jpet.aspetjournals.org/content/371/1/106.short 4100 - http://jpet.aspetjournals.org/content/371/1/106.full SO - J Pharmacol Exp Ther2019 Oct 01; 371 AB - 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 α1A-/α1D-AR and 5-HT1A receptors, and to estimate their affinity for D2, D3, and 5-HT1A receptors, which are putatively involved in ejaculatory dysfunction. Competition binding assays were performed with native (D2, 5-HT1A) or transfected (human α1A-, α1B-, α1Dt-AR, and D3) receptors for determination of the drug’s affinities. Tamsulosin and silodosin have the highest affinities for α1A-AR, but only silodosin is clearly a selective α1A-AR antagonist, with Ki ratios of 25.3 and 50.2 for the α1D- and α1B-AR, respectively. Tamsulosin, silodosin, and LDT5 (but not terazosin, doxazosin, and alfuzosin) have high affinity for the 5-HT1A receptor (Ki around 5–10 nM), behaving as antagonists. We conclude that the uroselectivity of tamsulosin is not explained by its too-low selectivity for the α1A- versus α1B-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.SIGNIFICANCE STATEMENT The present work revisits the uroselectivity of the five Food and Drug Administration–approved α1 adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Contrary to what has been claimed by some, our results indicate that the uroselectivity of tamsulosin is probably not fully explained by its too-weak selectivity for the α1A versus α1B adrenoceptors. We also show that tamsulosin affinity for D3 and 5-HT1A receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Based on our lead compound LDT5, present data support the search for a multitarget antagonist of α1A–α1D and 5-HT1A receptors with poor brain penetration as an alternative for BPH treatment.