Quantitative Structure-Activity Relationships and Eudismic Analyses of the Presynaptic Dopaminergic Activity and Dopamine D2 and σ Receptor Affinities of 3-(3-Hydroxyphenyl)piperidines and Octahydrobenzo[f]quinolines

Abstract

Data from the preceding paper3 were examined by QSAR and eudismic analyses. A fair parabolic relationship was found between the lipophilicity (measured by a RP-HPLC method) and the a-receptor affinity of 3-(3-hydroxyphenyl)piperidines (3HPP derivatives) and octahydrobenzo[f]quinolines (OHBQ derivatives). As far as the dopamine D2 receptor is concerned, the trans-7-hydroxy-OHBQ derivatives show a 10-fold higher affinity than the eutomeric S enantiomers of 3HPP derivatives, once lipophilicity has been accounted for. This difference in affinity is suggested to correspond to the energy necessary for the 3HPP derivatives to adopt the receptor-bound conformation. The R enantiomers of 3HPP derivatives display no apparent increase in D2 affinity with increasing lipophilicity, and indeed the eudismic index in this series increases with affinity (eudismic affinity quotient = 0.70), in agreement with a recent model of the binding of N-propy]-3HPP (3PPP) enantiomers to the D2 receptor. The selectivity in o-/D2 affinities was found to depend on both lipophilicity and configuration of the ligands; thus, the selectivity is maximal for log /ewvalues of ca. 1.7-2.1 and is much larger for the R than for the S enantiomers of 3HPP derivatives. © 1987, American Chemical Society. All rights reserved.