Ringdahl B, Jenden D J
J Med Chem. 1987 May;30(5):852-4. doi: 10.1021/jm00388a018.
An N-methyl-N-(2-bromoethyl)amino analogue (2) of oxotremorine cyclized in phosphate buffer to an aziridinium ion (3). The first-order rate constants (k1) for the cyclization reaction at 22 and 37 degrees C (pH 7.3) were 0.14 and 0.85 min-1, respectively. Determination of k1 as a function of pH gave a pKa value of 5.6 for 2. The rate constants (k2) for the hydrolysis of 3 at 22 and 37 degrees C (pH 7.3) were 0.0083 and 0.040 min-1, respectively. Compound 3 was 3-fold more active than oxotremorine as a muscarinic agonist on the guinea pig ileum, whereas its nicotinic actions, as estimated on the frog rectus, were quite weak. Because of its greater rate of cyclization and the higher peak concentrations of the aziridinium ion which ensue, 2 may offer advantages over its (2-chloroethyl)amino analogue (1) as an alkylating ligand for muscarinic receptors.
