M3 receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland
The antimuscarinic profile of the experimental drug solifenacin/YM905 [(+)-(1S,3′R)-quinuclidin-3′-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate] for the treatment of overactive bladder was compared with the commonly prescribed agent oxybutynin. In radioligand binding assays, pKi values of solifenacin for M1, M2, and M3 receptors were 7.6, 6.9, and 8.0, respectively. These values for oxybutynin were 8.6 (M1), 7.7 (M2), and 8.9 (M3). Solifenacin and oxybutynin antagonized the contractile effect of carbachol (CCh) on isolated guinea pig urinary bladder smooth muscle (detrusor), displaying the negative logarithm of antagonist apparent affinity constant (pKb value) of 7.1 for solifenacin and 7.4 for oxybutynin. To study the tissue selectivity between bladders and salivary glands, guinea pig detrusor and mouse submandibular gland cells were stimulated with CCh and monitored for intracellular Ca2+, as determined by Fura 2 fluorescence. Ca2+ mobilization of detrusor cells was inhibited equipotently by solifenacin (pKi=8.4) and oxybutynin (pKi =8.6), whereas that of the gland cells was antagonized less potently by solifenacin (pKb=7.4) than by oxybutynin (pKb=8.8), although the M3 subtype mediated both cell responses. In anesthetized rats, solifenacin (63–2100 nmol kg–1 or 0.03–1 mg kg–1) dose-dependently inhibited CCh-stimulated increases in urinary bladder pressure, while its inhibitory effects on salivation and bradycardia were apparent only at a dose of 2100 nmol kg–1. In contrast, oxybutynin within a dose range of 77–770 nmol kg–1 (0.03–0.3 mg kg–1) inhibited responses of the bladder and salivary gland slightly more potently than that of the heart. In addition, inhibitory effects of darifenacin indicated a major role of M3 receptors in the bladder and salivary gland. Therefore, M3 receptor antagonism by solifenacin could be bladder-selective. This selectivity remains to be elucidated and may provide new approaches to the pharmacotherapy of overactive bladder.
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