A theoretical and experimental study of the semirigid cholinergic agonist 3 acetoxyquinuclidine

The interaction of the two enantiomers 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.