N-[4-[(2-Chloroethyl)methylamino]-2-butynyl]-5-methyl-2-pyrrolidone (3) and N-[4-[(2-bromoethyl)methylamino]-2-butynyl]-5-methyl-2- pyrrolidone (4) were synthesized. Compounds 3 and 4 cyclized in neutral aqueous solution to an aziridinium ion (4A). The rate constants for the cyclization of 3 and 4 at 37 degrees C were 0.025 and 0.89 min-1, respectively. The aziridinium ion was equipotent with carbachol as a muscarinic agonist on the isolated guinea pig ileum. It was more potent than the corresponding 2-pyrrolidone derivative (2A) in alkylating muscarinic receptors in homogenates of the rat cerebral cortex. This higher potency was due to greater receptor affinity of 4A as compared to 2A rather than to greater rate constant for alkylation of muscarinic receptors. These properties of 3 and 4 and their low toxicity should make them valuable tools for receptor inactivation studies in vivo and in vitro.
        
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Ringdahl B, Roch M, Katz ED, Frankland MC (1989) Alkylating partial muscarinic agonists related to oxotremorine. N-[4-[(2-haloethyl)methylamino]-2-butynyl]-5-methyl-2-pyrrolidones Journal of Medicinal Chemistry32: 659-63
Ringdahl B, Roch M, Katz ED, Frankland MC (1989) Journal of Medicinal Chemistry32: 659-63