Ringdahl B, Mellin C, Ehlert F J, Roch M, Rice K M, Jenden D J
Department of Pharmacology, School of Medicine, University of California, Los Angeles 90024-1735.
J Med Chem. 1990 Jan;33(1):281-6. doi: 10.1021/jm00163a046.
4-[(2-Chloroethyl)methylamino]-2-butynyl N-(3-chlorophenyl)carbamate (2) and 4-[(2-bromoethyl)methylamino]-2-butynyl N-(3-chlorophenyl)carbamate (3) were synthesized. Compounds 2 and 3 cyclized at neutral pH to an aziridinium ion (4). The rate constants for the cyclization of 2 and 3 at 37 degrees C were about 0.01 and 0.4 min-1, respectively, as measured by titrimetric analysis and by 1H NMR spectroscopy. The aziridinium ion had 1/4 the potency of McN-A-343 (1) as a ganglionic muscarinic stimulant in the anesthetized, pentolinium-treated rat but showed no muscarinic effects on the isolated guinea pig ileum. It caused alkylation of muscarinic receptors in homogenates of the rat cerebral cortex. An irreversible blockade of central muscarinic receptors was also observed after intravenous administration of 3 to mice. Because of its selectivity, irreversible actions, and ability to pass into the central nervous system, 3 should become a valuable tool in studies of muscarinic receptors.
合成了4-[(2-氯乙基)甲基氨基]-2-丁炔基N-(3-氯苯基)氨基甲酸酯(2)和4-[(2-溴乙基)甲基氨基]-2-丁炔基N-(3-氯苯基)氨基甲酸酯(3)。化合物2和3在中性pH下环化生成氮丙啶离子(4)。通过滴定分析和1H NMR光谱法测得，2和3在37℃下的环化速率常数分别约为0.01和0.4 min-1。在麻醉的、用潘托铵处理的大鼠中，氮丙啶离子作为神经节毒蕈碱兴奋剂的效力是McN-A-343(1)的1/4，但对离体豚鼠回肠无蕈碱样作用。它导致大鼠大脑皮质匀浆中毒蕈碱受体的烷基化。给小鼠静脉注射3后，还观察到中枢毒蕈碱受体的不可逆阻断。由于其选择性、不可逆作用以及进入中枢神经系统的能力，3应成为研究毒蕈碱受体的有价值工具。
