Complementary molecular orbital investigations on the conformation of choline derivatives

Quantum-mechanical computations by the PCILO method, applied previously to the study of the conformational properties of acetylcholine and its derivatives modified in the central part of this molecule, are extended to modifications involving its cationic head and its ester terminal. The replacement of the methyl groups of the cationic head by hydrogens or ethyl groups leads to a steep decline in parasympathomimetic activity. It is shown that the triethyl derivative conserves the gauche form as the most stable one. The redistribution of the electronic charges at the onium group implies, however, a transition from an ionic to a hydrophobic binding. The replacement of the methyls by two or three hydrogens leads to a different preferred gauche-gauche conformation. The replacement of the methyl group at the ester terminal by a phenyl ring enables a comparison with the conformational properties of local anesthetics. The study brings about evidence, substantiated by NMR spectroscopy, that acetylcholine analogs and protonated local anesthetics are conformationally similar. Choline ethers also show a general preference for a gauche conformation. Nevertheless, biological studies do not indicate a constant correlation between conformation and biological potency. Conformational analogies or discrepancies alone cannot thus account for the fine details of the biological activity which must depend also on the electronic structure.This work was supported by the A.T.P. N A 655-2303 of the C.N.R.S.