Computational study on the conformations of dopamine, its α- and ortho-methylated derivatives and their N-protonated forms

Abstract

A comparative theoretical study of the conformational profiles of dopamine, its α-, 2-, and 6-methyl derivatives, for which D1-dopaminergic activities have been recorded, and their N-protonated forms, which predominate strongly at physiological pH, was carried out using the AM1 approximation and the COSMO model to evaluate the effects of an aqueous medium on intramolecular rotations. In the gas phase, for the neutral and N-protonated molecules, the perpendicular rotamers are generally more stable than the coplanar rotamers. In the N-protonated molecules, the gauche rotamers tend to be more stable than the trans forms, but in aqueous medium the trans rotamers are preferred. Taken together, our results support the contention that agonist activity at the D1 dopaminergic receptor involves the trans-β rotamer. For this set of compounds, activity is associated with a stable trans-β rotamer lying less than 1 kcal mol−1 above the global energy minimum, and lack of activity is a consequence of this conformation being inaccessible at body temperatures.