Pharmacological characteristics of indoline derivatives in muscarinic receptor subtypes

The present study was designed to investigate which muscarinic receptors the indoline derivatives interact with and also their pharmacological properties. Compounds I and II contracted guinea-pig ileum in a concentration-dependent manner, whereas compounds III-IX behaved as antagonists and Schild plots gave straight lines. 4-DAMP antagonized the contractile responses to compounds I and II, and the pA(2) values for 4-DAMP were 8.96 +/- 0.23 and 9.09 +/- 0.06, respectively. In guinea-pig left atrium, compound I partly inhibited twitch responses, whereas compound II did not have any effect. In rabbit vas deferens, compounds I and II produced inhibitory effects on twitch responses evoked by field stimulation. Pirenzepine antagonized the inhibitory responses of compounds I and II, and the pA(2) values for pirenzepine were 7.90 +/- 0.13 and 8.12 +/- 0.06, respectively. Compound I has about 150-fold higher affinity to M(1) receptors than to M(3) receptors, while compound II has about 360-fold higher affinity to M(1) receptors. Our results indicate that compounds I and II show 7- and 16-fold higher M(1) receptor selectivity than McN-A-343, respectively. Therefore, compound II is selective for M(1) receptors over M(2) or M(3) receptors.