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In vivo demonstration of M3 muscarinic receptor subtype selectivity of darifenacin in mice.
- Source :
-
Life sciences [Life Sci] 2006 Dec 14; Vol. 80 (2), pp. 127-32. Date of Electronic Publication: 2006 Sep 01. - Publication Year :
- 2006
-
Abstract
- A novel muscarinic receptor antagonist, darifenacin, inhibited specific binding of [N-methyl-(3)H]scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart in a concentration-dependent manner. The inhibitory effect was most potent in the submaxillary gland, followed by the bladder and heart. In addition, darifenacin inhibited specific [(3)H]NMS binding in the membranes of CHO-K1 cell lines expressing muscarinic M(2) and M(3) receptor subtypes, and the potency was significantly (22-fold) greater at the M(3) than at the M(2) subtype. At 0.5 to 12 h after oral administration of darifenacin, a significant increase in K(d) values for specific [(3)H]NMS binding was seen in the bladder, submaxillary gland and lung of mice, compared with control values. Also, there was a sustained decrease in the B(max) values in the submaxillary gland. These data suggest that muscarinic receptor binding of oral darifenacin is rapid in onset and of a long duration. On the other hand, oral darifenacin exerted only temporary or little binding of muscarinic receptors in the heart and colon. Pilocarpine-induced salivary secretion in mice was continuously suppressed by oral darifenacin. The time-course of suppression coincided well with that for the muscarinic receptor binding in the submaxillary gland. The antagonistic effect of darifenacin against the dose-response curves for pilocarpine appeared to be insurmountable. In conclusion, the present study has shown that oral darifenacin may exert a pronounced and long-lasting binding of muscarinic receptors in tissues expressing the M(3) subtype.
- Subjects :
- Administration, Oral
Animals
Binding, Competitive
CHO Cells
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Lung metabolism
Male
Mice
Mice, Inbred Strains
Muscarinic Agonists pharmacology
Pilocarpine pharmacology
Receptor, Muscarinic M2 biosynthesis
Receptor, Muscarinic M3 biosynthesis
Saliva metabolism
Submandibular Gland metabolism
Time Factors
Urinary Bladder metabolism
Benzofurans pharmacology
Muscarinic Antagonists pharmacology
Pyrrolidines pharmacology
Receptor, Muscarinic M3 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0024-3205
- Volume :
- 80
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 16996089
- Full Text :
- https://doi.org/10.1016/j.lfs.2006.08.028