Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists.

Abstract Tolterodine [( R )- N , N -diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was to compare the in vitro and in vivo antimuscarinic profiles of tolterodine with those of muscarinic receptor antagonists with distinct receptor subtype-selectivity profiles: darifenacin [( S )-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide; selective for muscarinic M 3 receptors]; UH-AH 37 (6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo-[ b , e ][1,4]diazepine-11-one; low affinity for muscarinic M 2 receptors); and AQ-RA 741 (11-({4-[4-(diethylamino)butyl]-1-piperidinyl}acetyl)-5,11-dihydro-6H-pyrido[2,3- b ][1,4]benzodiazepine-6-one; high affinity for muscarinic M 2 receptors). The in vitro profiles of these compounds were in agreement with previous reports; darifenacin and UH-AH 37 demonstrated selectivity for muscarinic M 3 /m3 over M 2 /m2 receptors, while the converse was observed for AQ-RA 741. In vivo, AQ-RA 741 was more potent (1.4–2.7-fold) in inhibiting urinary bladder contraction than salivation in the anaesthetised cat (i.e., a profile similar to that of tolterodine [2.5–3.3-fold]), while darifenacin and UH-AH 37 showed the reverse selectivity profile (0.6–0.8 and 0.4–0.5-fold, respectively). The results confirm that it is possible to separate the antimuscarinic effects on urinary bladder and salivary glands in vivo. The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M 3 /m3 over M 2 /m2 receptors may result in a more pronounced effect on salivation than on bladder contraction. The data on AQ-RA 741 may indicate that muscarinic M 2 /m2 receptors may have a role in bladder contraction.