The dopaminergic moiety of the ergots: a controversial topic studied with molecular mechanics

Conformational analyses of the side chain of model compounds of the in vivo active dopamine receptor agonist 4-[2-(di-n-propylamino)ethyl]indole (DPAI) were performed with molecular mechanics calculations. The results from these calculations, together with the possibility of meta hydroxylation of indoles in vivo, led to the proposal of fitting 6-hydroxy-4-[2-(di-n-propylamino)ethyl]indole (6-OH-DPAI), (S)-5-hydroxy-N,N-dialkyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-ylami nes and (S)-5-hydroxy-2-(dialkylamino)tetralins in a common concept, considering both stereochemistry and hydrogen-bond function in such an overlap. This study emphasizes the importance of considering both conformational analysis and the possibilities of metabolic activation when performing structure-activity studies based on flexible compounds and in vivo data. The answer to the question as to which part of the ergot molecule is responsible for its dopaminergic effect is thus ambiguous. It is possible that the pyrrolylethylamine moiety of the ergots contributes to both in vitro and in vivo effects, and that their 13-OH metabolites contribute, possibly significantly, to their in vivo effects.