Evaluation of a spin-labeled inhibitor of acetylcholinesterase

Abstract

This paper describes the synthesis of 1, a spin-labeled analog of N,N-dimethyl-2-phenyl-aziridinium chloride 2. The compound is formed in situ from 3b and acts as a poor competitive inhibitor of bovine erythrocyte acetylcholinesterase with a Ki value of M.

Synthesis of spin-labeled analogues of drug molecules with potential action on neuroreceptors

“…I x 10-3 M ) of bovine erythocyte acetylcholinesterase (14). The reason probably lies in the presence of a bulky spin label group on the aromatic ring.…”

“…This salt is expected to cyclize instantaneously to the aziridinium chloride salt in aqueous buffer above pH 7 (21). The synthesis of a similar molecule 11, but with the nitroxide function in a different position, has already been reported (14). Originally the synthesis of the SL-amine 11 was developed with the objective of probing the geometry of the anionic site of acetylcholinesterase since the corresponding N.Ndimethyl-2-phenylaziridinium chloride has been shown to be a potent anionic-site-directed irreversible inhibitor (21,22).…”

“…For example, a large number of drug analogues containing the nitroxide moiety have been synthesized and used to study the topography of specific binding sites in receptor macromolecules. ' The most representative efforts toward this goal include the preparation of SL-analogues of acetylcholine ( I -3), SL-quaternary ammonium ligands (4,5), SL-propranolol (6, 7), SL-narcotics (8), SL-steroids (9-1 I), SL-phenytoin (12), SL-penicillin (I:), and a SL-analogue of N,N-dimethyl-2-phenylaziridinium (14).…”