CONFORMATIONAL STUDIES ON THE 4 STEREOISOMERS OF THE NOVEL ANTICHOLINERGIC -(DIMETHYLAMINO)-2-PHENYL-2-(2-PYRIDYL)PENTANAMIDE

To interpret differences in the anticholinergic activity among the fou r stereoisomers of -(dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide (1-4), we performed conformational studies using the semiempirical mol ecular orbital method. The structures of the global minimum-energy con formations obtained for 1-4, however, could not explain the different activities, particularly in terms of distances between the essential p harmacophores. We thus implemented superimposition studies, using the energetically stable conformations of the most active stereoisomer, 1( 2S,4R), as a template. The energy penalties for a conformation change of the less active stereoisomers 2-4 from their global minimum-energy structure to a new conformation, fitting onto the global minimum-energ y conformation of 1, appear to account for the differences in the phar macological potency better than using the other conformations of 1 as a template. We thus presume that the global minimum-energy conformatio n of 1 is closely related to the bioactive conformation for these anti cholinergics, and also that the pharmacological potency is linked to h ow readily these substances can change their conformations to fit the muscarinic receptor.