Molecular Pharmacology, Vol 11, 671-689, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

A Theoretical and Experimental Study of the Semirigid Cholinergic Agonist 3-Acetoxyquinuclidine

¹ Department of Chemistry, Technion-Israel Institute of Technology, Haifa; Department of Pharmacology, Mount Sinai School of Medicine, City University of New York; and Department of Biochemistry, George S. Wise Center for Life Sciences, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

The interaction of the two enantiomens of 3-acetoxyquinuclidine (3-AcQ) and of its N-methyl derivative with the cholinergic receptor and with cholinesterases was investigated experimentally in systems which respond to acetylcholine (ACh). Molecular structural factors which are conducive to the well-defined ACh-like activity were studied by quantum mechanical methods. The flexible moiety in the semirigid structure of 3-AcQ was shown to permit molecular rearrangements, as required for receptor activation, and to adopt an ACh-like conformation in the energetically preferred geometry. The interaction pharmacophore of the active species, defined by the electrostatic potential fields generated in their surroundings, revealed a reactivity pattern identical with that of ACh. The interaction pharmacophore of the N-methyl derivative of 3-AcQ was shown to be much less compatible with the requirements for ACh-like activity. The structural correlation between the ACh-like pattern of the drugs and the biological activity of related psychotropic-anticholinergic amino esters is discussed.