Antiviral Agents. II. Substituted Morpholinium Quaternary Salts

Anderson, Elvin L.; Casey, John E.; Force, Elizabeth E.; Jensen, Elizabeth; Matz, Ralph S.; Rivard, Donald E.

doi:10.1021/jm00320a013

Cited by 7 publications

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“…Syntheses and Structure of Hemicholiniums. The syntheses of 6-14 require 2-(N,lV-dimethylamino)ethanol and the appropriate bromomethyl ketone (21). The exception is the synthesis of 11, in which chloroethanal is generated in situ from hydrolysis of chloroethanal dimethyl acetal.…”

Section: Resultsmentioning

confidence: 99%

“…That solution was vapor diffused with Et^O/THF (1:1) at 25 °C to yield 1.73 g (83.8%) of colorless crystals: mp [196][197] °C [lit. (21) (E) 4,4-Dimethyl-2-hydroxy-2-(4-cyanophenyl)morpholinium Bromide (9). A solution of DMAE (0.10 mL, I.…”

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confidence: 99%

“…That solution was vapor diffused with Et^O/THF (1:1) at 25 °C to yield 6.03 g (90.1%) of clear yellow crystals: mp 210 °C dec [lit. (21) (G) 2-Hydroxy-4,4-dimethylmorpholinium Chloride (11). Chloroethanal dimethyl acetal (74 g, 600 mmol) was combined with 100 mL of 18% hydrochloric acid.…”

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Inhibition of acetylcholinesterase by hemicholiniums, conformationally constrained choline analogs. Evaluation of aryl and alkyl substituents. Comparisons with choline and (3-hydroxyphenyl)trimethylammonium

Stelly¹,

Colucci²,

Garcia³

et al. 1992

Chem. Res. Toxicol.

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2-Substituted-2-hydroxy-4,4-dimethylmorpholiniums (hemicholiniums) inhibit acetylcholinesterase (EC 3.1.1.7)-catalyzed hydrolysis of acetylthiocholine (ATCh). The 4-substituted arenes [NH2, NHC(O)CH3, Cl, CN, and NO2] have values of inhibition constants (Ki) that range from 220 to 3690 microM, which correlate with Hammett sigma, rho approximately 0.8. The alkyl compounds, hydrogen, methyl, tert-butyl, and trifluoromethyl, have values of Ki of 550, 560, 1200, and 1200 microM, respectively. These values compare favorably with Ki = 960 microM for choline. The conformation of AChE-bound choline must be gauche to support our suggestion that hemicholiniums are conformationally constrained analogues of choline. (3-Hydroxyphenyl)trimethylammonium (5) inhibits most strongly, Ki = 0.21 microM, of the compounds examined in this study. The solvent isotope effect (H2OKi/D2OKi = 0.83 +/- 0.04) suggests that inhibition by 5 involves hydrogen bonding. The binding by AChE of the hemicholiniums of various sizes and the strong binding of 5 support an earlier proposal [Schowen, K. B., Smissman, E. E., and Stephen, W. F., Jr. (1975) J. Med. Chem. 18, 292-300] that the active site of AChE has ample space for rotation about the C-C bond in choline. Compound 5, which has one more carbon between the hydroxy and trimethylammonium than does choline, inhibits much more potently than either choline or the hemicholiniums. Compound 5 provides a correct spacer to span the trimethylammonium recognition site and the esteratic site of AChE. This aromatic spacer interacts favorably with the hydrophobic active site, and the phenolic hydroxyl probably hydrogen bonds to the histidine in the esteratic site. Choline in any conformation and the hemicholiniums are too short to make a strong hydrogen bond.

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