Kinetics of activation and in vivo muscarinic receptor binding of N-(2-bromoethyl)-4-piperidinyl diphenylacetate: an analog of 4-DAMP mustard.
4-DAMP mustard (N-2-chloroethyl)-4-piperidinyl diphenylacetate) has been shown to selectively and irreversibly inhibit muscarinic receptors. In an attempt to increase the rate of formation and peak concentration of the reactive intermediate, an analog [N-(2-bromoethyl)-4-piperidinyl diphenylacetate (4-DAMP bromo mustard)] was synthesized and the molecular formula confirmed by mass analysis. The 4-DAMP bromo mustard was shown to cyclize in phosphate buffer (pH 7.4) to the corresponding aziridinium ion with a first-order rate constant (k1) of 0.071 min-1 at 0 degrees C. At 25 degrees C and 37 degrees C, the formation of the aziridinium ion was nearly instantaneous (100% cyclized within 15 sec) at neutral pH. The rate constants (k2) for the hydrolysis of the aziridinium ion at 25 degrees C and 37 degrees C (pH 7.4) were 0.0027 and 0.010 min-1, respectively, in excellent agreement with the published rate constants for the hydrolysis of the aziridinium ion formed from 4-DAMP mustard. In vivo treatment with 4-DAMP bromo mustard in rats resulted in irreversible inhibition of muscarinic receptor binding in peripheral, but not central nervous system, tissues, suggesting that the quickly formed aziridinium ion does not penetrate the blood-brain barrier.
Griffin
M T
MT
Department of Chemistry, Chapman University, Orange, California.
Thomas
E A
EA
Ehlert
F J
FJ
D000818:Animals; D001388:Aziridines / Q000378:metabolism; D004158:Diphenylacetic Acids / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D016548:Prosencephalon / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000145:classification / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism / Q000648:ultrastructure
D001388:Aziridines; D004158:Diphenylacetic Acids; D010880:Piperidines; D011976:Receptors, Muscarinic; C074183:N-(2-chloroethyl)-4-piperidinyl diphenylacetate; C082230:N-(2-bromoethyl)-4-piperidinyl diphenylacetate