Zorn S H, Duman R S, Giachetti A, Micheletti R, Giraldo E, Krogsgaard-Larsen P, Enna S J
J Pharmacol Exp Ther. 1987 Jul;242(1):173-8.
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.
先前的报道表明，（R）-哌啶甲酸乙酯乙酯[（R）-NAEE]在体内具有拟胆碱特性。本研究旨在通过在一些胆碱能作用的药理学和生化试验中检测（R）-NAEE的作用，更全面地描述这种作用。发现（R）-NAEE对豚鼠心房产生负性肌力和负性变时作用（pD2分别为5.91和5.62），并且在与氨甲酰甲胆碱相似的浓度下能够刺激豚鼠回肠（pD2 = 5.95）和大鼠空肠（pD2 = 5.40）的收缩。（R）-NAEE的心脏和肠道作用均被阿托品逆转。此外，（R）-NAEE在多种组织中与N-[3H]甲基东莨菪碱和[3H]哌仑西平竞争毒蕈碱结合位点。与卡巴胆碱一样，（R）-NAEE抑制大鼠纹状体膜中GTP刺激的腺苷酸环化酶（EC50 = 52 microM），而与卡巴胆碱不同的是，（R）-NAEE不能刺激大鼠大脑皮层切片中肌醇磷酸的积累，在后者系统中表现为拮抗剂（pA2 = 5.0）。结果表明，（R）-NAEE直接与胆碱能毒蕈碱受体相互作用，是M2亚型的激动剂和M1位点的拮抗剂。
