title: Pharmacological characteristics of indoline derivatives in muscarinic receptor subtypes.
abstract: 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 pA2 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 pA2 values for pirenzepine were 7.90 +/- 0.13 and 8.12 +/- 0.06, respectively. Compound I has about 150-fold higher affinity to M1 receptors than to M3 receptors, while compound II has about 360-fold higher affinity to M1 receptors. Our results indicate that compounds I and II show 7- and 16-fold higher M1 receptor selectivity than McN-A-343, respectively. Therefore, compound II is selective for M1 receptors over M2 or M3 receptors.
authors.affiliation: Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Adachi
authors.forename: K
authors.initials: K
authors.lastname: Koike
authors.forename: I
authors.initials: I
authors.lastname: Takayanagi
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D007211:Indoles; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; C057812:indoline; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium