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dc.contributor.authorQuaresma, Bruna Maria Castro Salomão
dc.contributor.authorPimenta, Amanda Reis
dc.contributor.authorSantos da Silva, Anne Caroline
dc.contributor.authorPupo, André Sampaio [UNESP]
dc.contributor.authorRomeiro, Luiz Antonio S.
dc.contributor.authorSilva, Claudia Lucia Martins
dc.contributor.authorNoël, François
dc.identifier.citationJournal of Pharmacology and Experimental Therapeutics, v. 371, n. 1, p. 106-112, 2019.
dc.description.abstracta1-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 a1-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 a1-AR subtype selectivity as well as of LDT5 (1-(2-methoxyphenyl)-4-[2-(3,4-dimethox-yphenyl) ethyl]piperazine monohydrochloride), a compound previously described as a multitarget antagonist of a1A-/a1D-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 a1A-, a1B-, a1Dt-AR, and D3) receptors for determination of the drug’s affinities. Tamsulosin and silodosin have the highest affinities for a1A-AR, but only silodosin is clearly a selective a1A-AR antagonist, with Ki ratios of 25.3 and 50.2 for the a1D- and a1B-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 a1A- versus a1B-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.en
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
dc.relation.ispartofJournal of Pharmacology and Experimental Therapeutics
dc.titleRevisiting the pharmacodynamic uroselectivity of a1-adrenergic receptor antagonistsen
dc.contributor.institutionFederal University of Rio de Janeiro
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversidade de Brasília (UnB)
dc.description.affiliationLaboratory of Biochemical and Molecular Pharmacology Institute of Biomedical Sciences Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373
dc.description.affiliationDepartment of Pharmacology Instituto de Biociências UNESP
dc.description.affiliationHealth Sciences Faculty Universidade de Brasília
dc.description.affiliationUnespDepartment of Pharmacology Instituto de Biociências UNESP
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