Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

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Di Salvo J, Nagabukuro H, Wickham LA, Abbadie C, DeMartino JA, Fitzmaurice A, Gichuru L, Kulick A, Donnelly MJ, Jochnowitz N, Hurley AL, Pereira A, Sanfiz A, Veronin G, Villa K, Woods J, Zamlynny B, Zycband E, Salituro GM, Frenkl T, Weber AE, Edmondson SD, Struthers M

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

J Pharmacol Exp Ther. 2017 Feb;360(2):346-355. doi: 10.1124/jpet.116.237313. Epub 2016 Dec 13.

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27965369 [ View in PubMed
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Abstract

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of beta3-adrenergic receptors (beta3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel beta3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of beta3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full beta3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a beta3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel beta3AR agonist probe, [(3)H]MRL-037, that selectively labels beta3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of beta3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

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