title: (R)-nipecotic acid ethyl ester: a direct-acting cholinergic agonist that displays greater efficacy at M2 than at M1 muscarinic receptors.
abstract: Previous reports have suggested that the ethyl ester of (R)-nipecotic acid ethyl ester [(R)-NAEE] displays cholinomimetic properties in vivo. The present study was undertaken to characterize more fully this action by examining the effects of (R)-NAEE in a number of pharmacological and biochemical tests of cholinergic action. (R)-NAEE was found to produce negative inotropic and chronotropic effects on the guinea pig atria (pD2 = 5.91 and 5.62, respectively), and was capable of stimulating contractions in the guinea pig ileum (pD2 = 5.95) and rat jejunum (pD2 = 5.40) at concentrations similar to bethanechol. Both the cardiac and intestinal effects of (R)-NAEE were reversed by atropine. Moreover, (R)-NAEE competed with N-[3H]methylscopolamine and [3H]pirenzepine for muscarinic binding sites in a variety of tissues. Like carbachol, (R)-NAEE inhibited GTP-stimulated adenylate cyclase in rat striatal membranes (EC50 = 52 microM), whereas, unlike carbachol, (R)-NAEE was unable to stimulate inositol phosphate accumulation in rat cerebral cortical slices, behaving as an antagonist in this latter system (pA2 = 5.0). The results indicate that (R)-NAEE interacts directly with cholinergic muscarinic receptors, being an agonist for the M2 subtype and an antagonist at M1 sites.
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D018723:Bethanechol; D001626:Bethanechol Compounds / Q000494:pharmacology; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D003864:Depression, Chemical; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D007583:Jejunum / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009557:Nipecotic Acids / Q000378:metabolism / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000502:physiology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D001626:Bethanechol Compounds; D009557:Nipecotic Acids; D010710:Phosphates; D011976:Receptors, Muscarinic; D018723:Bethanechol; C038002:nipecotic acid ethyl ester; D006160:Guanosine Triphosphate; D002217:Carbachol