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Revisiting the Pharmacodynamic Uroselectivity of α 1-Adrenergic Receptor Antagonists.
J Pharmacol Exp Ther. 2019 10; 371(1):106-112.JP

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 α 1-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 α 1-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-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 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-HT1A 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. 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.

Authors+Show Affiliations

Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).Laboratory of Biochemical and Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (B.M.C.S.Q., A.R.P., A.C.S.d.S., C.L.M.S., F.N.); Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, Brazil (A.S.P.); and Health Sciences Faculty, Universidade de Brasília, Brasília, Brazil (L.A.S.R.) fnoel@pharma.ufrj.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31285236

Citation

Quaresma, Bruna Maria Castro Salomão, et al. "Revisiting the Pharmacodynamic Uroselectivity of Α 1-Adrenergic Receptor Antagonists." The Journal of Pharmacology and Experimental Therapeutics, vol. 371, no. 1, 2019, pp. 106-112.
Quaresma BMCS, Pimenta AR, Santos da Silva AC, et al. Revisiting the Pharmacodynamic Uroselectivity of α 1-Adrenergic Receptor Antagonists. J Pharmacol Exp Ther. 2019;371(1):106-112.
Quaresma, B. M. C. S., Pimenta, A. R., Santos da Silva, A. C., Pupo, A. S., Romeiro, L. A. S., Silva, C. L. M., & Noël, F. (2019). Revisiting the Pharmacodynamic Uroselectivity of α 1-Adrenergic Receptor Antagonists. The Journal of Pharmacology and Experimental Therapeutics, 371(1), 106-112. https://doi.org/10.1124/jpet.119.260216
Quaresma BMCS, et al. Revisiting the Pharmacodynamic Uroselectivity of Α 1-Adrenergic Receptor Antagonists. J Pharmacol Exp Ther. 2019;371(1):106-112. PubMed PMID: 31285236.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Revisiting the Pharmacodynamic Uroselectivity of α 1-Adrenergic Receptor Antagonists. AU - Quaresma,Bruna Maria Castro Salomão, AU - Pimenta,Amanda Reis, AU - Santos da Silva,Anne Caroline, AU - Pupo,André Sampaio, AU - Romeiro,Luiz Antonio S, AU - Silva,Claudia Lucia Martins, AU - Noël,François, Y1 - 2019/07/08/ PY - 2019/05/21/received PY - 2019/07/02/accepted PY - 2019/7/10/pubmed PY - 2020/4/21/medline PY - 2019/7/10/entrez SP - 106 EP - 112 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 371 IS - 1 N2 - 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 α 1-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 α 1-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-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 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-HT1A 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. 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/31285236/Revisiting_the_Pharmacodynamic_Uroselectivity_of_α_1-Adrenergic_Receptor_Antagonists L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=31285236 DB - PRIME DP - Unbound Medicine ER -