199658-60-1Relevant academic research and scientific papers
Change in the mode of inhibition of acetylcholinesterase by (4- nitrophenyl)sulfonoxyl derivatives of conformationally constrained choline analogues
Savle, Prashant S.,Medhekar, Rohit A.,Kelley, Ella L.,May, Jerome G.,Watkins, Steven F.,Fronczek, Frank R.,Quinn, Daniel M.,Gandour, Richard D.
, p. 19 - 25 (1998)
A chiral, five-step synthesis of 2-(hydroxymethyl)-2,4- dimethylmorpholine (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 2,4-dimethyl-2-[[(4-nitrophenyl)sulfonoxy]- methyl]morpholine (14). The tertiary morpholines 12, 14, and 15 are quaternarized to afford 2-(hydroxymethyl)-2,4,4-trimethylmorpholinum iodide (2), 2,4,4-trimethyl-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 inhibitors are compared with conformationally constrained aryl hemicholinium ACHE inhibitors. Enantiomers of 2 and 4 are reversible competitive inhibitors of ACHE, with values of K(i) = 360 ± 30 μM for (S)- 2, 650 ± 90 μM for (R)-2, 450 ± 70 μM for (S)-4, and 560 ± 30 μM for (R)-4, respectively. Enantiomers of 3 are noncompetitive inhibitors of AChE with values of K(i) = 19.0 ± 0.9 μM for (S)-3 and 50 ± 2 μM for (R)-3, respectively. AChE shows a 2-fold chiral discrimination in the case of inhibition by 2 and 3. Inhibition also changes from competitive to noncompetitive when (3-hydroxyphenyl)-N,N,N-trimethylammonium iodide (18) [K(i) = 0.21 ± 0.06 μM; 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 [3-[(4-nitrophenyl)sulfonoxy]-phenyl]-N,N,N- trimethylammonium iodide (5), K(i) = 6.0 ± 0.5 μM. These results indicate that the 4-nitrobenzenesulfonyl group controls the mode of inhibition.
