Antagonism of?1-adrenoceptors by?3-adrenergic agonists: Structure-function relations of different agonists in prostate smooth muscle contraction

Huang, Ru; Tamalunas, Alexander; Waidelich, Raphaela; Strittmatter, Frank; Stief, Christan G. und Hennenberg, Martin (2022): Antagonism of?1-adrenoceptors by?3-adrenergic agonists: Structure-function relations of different agonists in prostate smooth muscle contraction. In: Biochemical Pharmacology, Bd. 202, 115148

Abstract

Effects of beta 3-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several beta 3-adrenergic agonists include antagonism of alpha 1-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some beta 3-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of beta 3-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by alpha 1-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 mu M) right-shifted concentration responses curves for alpha 1-adrenergic agonists, resulting in increased EC50 values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting Emax values. ZD7114 (10 mu M) inhibited EFS-induced contractions, resulting in reduced Emax values. All effects of ZD7114 were resistant to the beta 3-adrenergic antagonist L-748337, including increases in EC50 values for alpha 1-adrenergic agonists, up to more than two magnitudes. Using 10 mu M, neither ZD2079, BRL37344 or CL316243 affected alpha 1-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 mu M) right-shifted concentration response curves for phenylephrine, increased EC50 values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 mu M) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart alpha 1-adrenoceptor antagonism to beta 3-agonists. Effects of beta 3-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including alpha 1-adrenoceptor antagonism by ZD7114 and BRL37344.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-2952
• Sprache: Englisch