Molecular Pharmacology, Vol 8, 612-622, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Further Molecular Orbital Studies on the Conformation of Acetylcholine and Its Derivatives

¹ Institut de Biologie Physico-Chimique, Laboratoire de Biochimie Théorique Associé au Centre National de la Recherche Scientifique, Paris 5^[unknown], France

The conformational properties of acetylcholine have been studied theoretically by a number of empirical and quantum-mechanical computational procedures. Comparison of the available results reveals significant discrepancies, particularly in their prediction of the global energy minimum (the preferred conformation). First, when the obviously unsatisfactory older empirical computations are disregarded, re-examination of the problem indicates that these discrepancies may be explained by the use of different geometrical input data by different groups of authors.

Second, calculations by the quantum-mechanical method of perturbative configuration interaction using localized orbitals PCILO have been extended to a series of acetylcholine derivatives: carbamoylcholine, - and -methylacetylcholine, ,-dimethylacetylcholine, and choline. Two distinct maps have been constructed for cases in which two molecules with different conformations exist ill the crystalline unit or for which different diastereoisomers are known. The results indicate that the conformational maps of these derivatives differ, some of them very significantly, from the map of acetylcholine. Thus the derivatives manifest a variety of different global energy minima (i.e., of preferred conformations), which, depending on the structure, may be of the gauche or the trans type. These compounds also exhibit distinct differences in energy barriers. It is concluded that detailed information about their conformational preferences and energy barriers requires their individual investigation. It is also shown that although the fundamental acetylcholine skeleton may be considered flexible, the degree of conformational freedom varies greatly from one derivative to another.

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ACKNOWLEDGMENTS The authors wish to thank Drs. D. L. Beveridge, M. Bossa, A. Damiani, A. Saran, and G. Govil for communication of data prior to their publication.