Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Compounds with high affinity for muscarinic M3 receptors have been used for many years to treat conditions associated with altered smooth muscle tone or contractility such as urinary urge incontinence, irritable bowel syndrome or chronic obstructive airways disease. M3 selective antagonists have the potential for improved toleration when compared with non-selective compounds. Darifenacin has high affinity (pKi 9.12) and selectivity (9 to 74-fold) for the human cloned muscarinic M3 receptor. Consistent with this profile, the compound potently inhibited M3 receptor mediated responses of smooth muscle preparations (guinea pig ileum, trachea and bladder, pA2 8.66 to 9.4) with selectivity over responses mediated through the M1 (pA2 7.9) and M2 receptors (pA2 7.48). Interestingly, darifenacin also exhibited functional tissue selectivity for intestinal smooth muscle over the salivary gland. The M3 over M1 and M2 selectivity of darifenacin was confirmed in a range of animal models. In particular, in the conscious dog darifenacin inhibited intestinal motility at doses lower than those which inhibit gastric acid secretion (M1 response), increase heart rate (M2 response) or inhibit salivary secretion. Clinical studies are ongoing to determine if darifenacin has improved efficacy and or toleration when compared with non-selective agents.
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PMID:Muscarinic antagonists in development for disorders of smooth muscle function. 1006 2

Although in vitro studies show that muscarinic M(3) receptors primarily mediate the effects of acetylcholine on gastrointestinal contractility, the muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that muscarinic M(3)-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal transit, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n = 16), the M(3) antagonist darifenacin ER [7.5 mg (n = 20) or 15 mg daily (n = 17)], or the nonspecific antagonist tolterodine [4 mg daily (n = 19)] for 6 days. Bowel habits were recorded by daily diaries. Both doses of darifenacin substantially delayed [P < 0.01 vs. placebo (for both doses), P < 0.01 vs. tolterodine (for 15 mg)] small intestinal transit, i.e., colonic filling at 6 h (placebo [59.6 +/- 6.4%, mean +/- SE], 7.5 mg ER [34.4 +/- 6.1%], 15 mg ER [20.4 +/- 6.3%)]. Darifenacin (15 mg) also delayed (P < 0.01 vs. placebo and tolterodine) half-time for ascending colonic emptying [placebo (12.0 +/- 1.5 h), 7.5 mg (18.6 +/- 1.9 h), 15 mg (22.9 +/- 2.6 h)] and colonic transit (geometric center) at 24 [placebo (2.8 +/- 0.2), 7.5 mg (2.4 +/- 0.2), 15 mg (1.9 +/- 0.2)] but not 48 h. Darifenacin did not affect gastric emptying and tolterodine did not affect bowel habits or gastrointestinal transit. With muscarinic antagonists used at clinically approved doses, these findings demonstrate that muscarinic M(3) receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses that affect small and large intestinal transit, M(3) antagonists do not affect gastric emptying in humans. The efficacy of darifenacin in diarrhea-predominant irritable bowel syndrome should be evaluated.
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PMID:Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans. 2039 37