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Metadados | Descrição | Idioma |
---|---|---|
Autor(es): dc.contributor | Federal University of Rio de Janeiro | - |
Autor(es): dc.contributor | Universidade Estadual Paulista (Unesp) | - |
Autor(es): dc.contributor | Universidade de Brasília (UnB) | - |
Autor(es): dc.creator | Quaresma, Bruna Maria Castro Salomão | - |
Autor(es): dc.creator | Pimenta, Amanda Reis | - |
Autor(es): dc.creator | Santos da Silva, Anne Caroline | - |
Autor(es): dc.creator | Pupo, André Sampaio [UNESP] | - |
Autor(es): dc.creator | Romeiro, Luiz Antonio S. | - |
Autor(es): dc.creator | Silva, Claudia Lucia Martins | - |
Autor(es): dc.creator | Noël, François | - |
Data de aceite: dc.date.accessioned | 2022-02-22T00:32:51Z | - |
Data de disponibilização: dc.date.available | 2022-02-22T00:32:51Z | - |
Data de envio: dc.date.issued | 2020-12-11 | - |
Data de envio: dc.date.issued | 2020-12-11 | - |
Data de envio: dc.date.issued | 2019-01-01 | - |
Fonte completa do material: dc.identifier | http://dx.doi.org/10.1124/jpet.119.260216 | - |
Fonte completa do material: dc.identifier | http://hdl.handle.net/11449/201189 | - |
Fonte: dc.identifier.uri | http://educapes.capes.gov.br/handle/11449/201189 | - |
Descrição: dc.description | a1-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. | - |
Descrição: dc.description | Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) | - |
Descrição: dc.description | Laboratory of Biochemical and Molecular Pharmacology Institute of Biomedical Sciences Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 | - |
Descrição: dc.description | Department of Pharmacology Instituto de Biociências UNESP | - |
Descrição: dc.description | Health Sciences Faculty Universidade de Brasília | - |
Descrição: dc.description | Department of Pharmacology Instituto de Biociências UNESP | - |
Formato: dc.format | 106-112 | - |
Idioma: dc.language | en | - |
Relação: dc.relation | Journal of Pharmacology and Experimental Therapeutics | - |
???dc.source???: dc.source | Scopus | - |
Título: dc.title | Revisiting the pharmacodynamic uroselectivity of a1-adrenergic receptor antagonists | - |
Tipo de arquivo: dc.type | livro digital | - |
Aparece nas coleções: | Repositório Institucional - Unesp |
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