CHANGE IN THE MODE OF INHIBITION OF ACETYLCHOLINESTERASE BY (4-NITROPHENYL)SULFONOXYL DERIVATIVES OF CONFORMATIONALLY CONSTRAINED CHOLINE ANALOGS

A chiral, five-step synthesis of 2-(hydroxymethyl)-2,4-dimethylmorphol ine (12) from (R)- and (S)-2-methylglycidols gives an overall yield of 63%. Morpholines (R)- and (S)-12 are converted into 2-(azidomethyl)-2 ,4-dimethylmorpholine (15) via hyl-2-[[(4-nitrophenyl)sulfonoxy]methyl ]morpholine (14). The tertiary morpholines 12, 14, and 15 are quaterna rized to afford 2-(hydroxymethyl)-2,4,4-trimethylmorpholinum iodide (2 ), l-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholinium iodide (3), and 2-(azidomethyl)-2,4,4-trimethylmorpholinium iodide (4), respectively, which all inhibit acetylcholinesterase (AChE). These morpholinium inhi bitors are compared with conformationally constrained aryl hemicholini um AChE inhibitors. Enantiomers of 2 and 4 are reversible competitive inhibitors of AChE, with values of K-i = 360 +/- 30 mu M for (S)-2, 65 0 +/- 90 mu M for (R)-2, 450 +/- 70 mu M for (S)-4, and 560 +/- 30 mu M for (R)-4, respectively. Enantiomers of 3 are noncompetitive inhibit ors of AChE with values of K-i = 19.0 +/- 0.9 mu M for (S)-3 and 50 +/ - 2 mu M for (R)-3, respectively. AChE shows a 2-fold chiral discrimin ation in the case of inhibition by 2 and 3. Inhibition also changes fr om competitive to noncompetitive when (3-hydroxyphenyl)-N,N,N-trimethy lammonium iodide (18) [K-i = 0.21 +/- 0.06 mu M; Lee, B. H., Stelly, T . C., Colucci, W. J., Garcia, J. G., Gandour, R. D., and Quinn, D. M. (1992) Chem. Res. Toxicol. 5, 411-418] is converted into rophenyl)sulf onoxy]phenyl]-N,N,N-trimethylammonium iodide (5) K-i = 6.0 +/- 0.5 mu M. These results indicate that the 4-nitrobenzenesulfonyl group contro ls the mode of inhibition.