Abstract

The conformational and electronic properties of acetylcholine, muscarine, and nicotine have been investigated by the quantum mechanical method of perturbative configuration interaction using localized orbitals. The results obtained in the field of preferred conformations, in particular in the case of acetylcholine, are in satisfactory agreement with experimental observations based on X-ray data. The distribution of the net electronic charges indicates, among other conclusions, the nearly neutral character of the quaternary nitrogen, the distribution of a large fraction (70-80%) of the formal positive charge of this nitrogen on the surrounding alkyl groups, producing a large cationic globe, and the near equivalence of the net total negative charges on the 2 oxygen atoms of acetylcholine. Altogether, the results do not favor a primordial role played by changes of conformation in the interactions of acetylcholine with different cholinergic nerve receptors, although some such changes may occur because of the appreciable flexibility of this molecule. They point rather to the importance in this respect of the electronic characteristics of the molecule. Thus, the involvement of the cationic globe in interactions with all cholinergic nerve receptors and that of the carbonyl and ester oxygens of acetylcholine in interactions with the nicotinic and muscarinic receptors, respectively, seems plausible.