A molecular mechanics approach to the understanding of presynaptic selectivity for centrally acting dopamine receptor agonists of the phenylpiperidine series.

Molecular mechanics (MMP2) calculated geometries and conformational energies have been employed in an attempt to elucidate the molecular basis for presynaptic dopamine receptor selectivity of centrally acting agonists of the phenylpiperidine series. A receptor interaction model based on the McDermed receptor concept, on superimpositions of calculated structures, and on conformational analysis is presented. The model focuses on the interaction between N-alkyl substituents and the receptor. From comparisons with rigid structures having either agonistic or antagonistic properties it is concluded that the presynaptically selective compound (S)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S)-3PPP) is acting as an agonist in one rotameric form and as an antagonist in another one. The selectivity of (S)-3PPP and the nonselectivity of its enantiomer are suggested to be due to differences in the interactions between N-alkyl substituents and the receptor. The receptor model presented led to the hypothesis that the piperidine ring in the compounds studied should be equivalent to a N-methyl group in its receptor interactions. Examples are given in support of this idea. Presynaptic selectivity was predicted for an aminotetralin derivative and was also observed in subsequent testing.