CONFORMATIONAL, AQUEOUS SOLVATION, AND PK(A), CONTRIBUTIONS TO THE BINDING AND ACTIVITY OF COCAINE, WIN-32-065-2, AND THE WIN VINYL ANALOG

Conformational properties of cocaine, WIN 32 065-2, and the WIN vinyl analog were studied via Austin Model 1 (AM1) semiempirical calculations. The conformational space of the molecules, as defined by the dihedral angles representing the orientation of the 2 beta and 3 beta side chains, was calculated on a 13 x 13 grid in the gas phase and included full geometry optimization at each grid point. Aqueous solvation energy surfaces were obtained using the AM1-Solvation Model 2 (AM1-SM2). The lowest energy points from the surfaces were fully optimized in both the gas and aqueous phases. Results predict the minimum 2 beta and 3 beta side chain conformations to be similar between the gas and aqueous phases and between the three molecules studied. A detailed analysis of the relationship of structural contributions to changes in conformational properties is presented. population analysis of the minimum energy regions indicates the neutral forms of WIN and the WIN vinyl analog to be more conformationally restricted than cocaine. This conformational restriction is related to steric interactions between the 2 beta and 3 beta moieties of the WIN compounds. Cocaine is calculated to be more favorably solvated than the WIN compounds due to the presence of the ester groups in the 2 beta and 3 beta moieties. The calculations predict the pK(a)s of the tropane nitrogen of the WIN compounds to be higher than in cocaine. A model is presented relating the decreased conformational flexibility, decreased aqueous solvation, and increased pK(a)s of the WIN compounds to their increased binding affinity to the cocaine receptor. Based on the present results, separate models are presented for binding of the neutral and protonated forms of cocaine to the receptor.