title: Quantitative structure-activity relationships and eudismic analyses of the presynaptic dopaminergic activity and dopamine D2 and sigma receptor affinities of 3-(3-hydroxyphenyl)piperidines and octahydrobenzo[f]quinolines.
abstract: Data from the preceding paper were examined by QSAR and eudismic analyses. A fair parabolic relationship was found between the lipophilicity (measured by a RP-HPLC method) and the sigma-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-propyl-3HPP (3PPP) enantiomers to the D2 receptor. The selectivity in sigma/D2 affinities was found to depend on both lipophilicity and configuration of the ligands; thus, the selectivity is maximal for log kw values of ca. 1.7-2.1 and is much larger for the R than for the S enantiomers of 3HPP derivatives.
authors.affiliation: School of Pharmacy, University of Lausanne, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Van de Waterbeemd
authors.forename: N
authors.initials: N
authors.lastname: el Tayar
authors.forename: B
authors.initials: B
authors.lastname: Testa
authors.forename: H
authors.initials: H
authors.lastname: Wikström
authors.forename: B
authors.initials: B
authors.lastname: Largent
mesh_terms: D010616:Phenanthrenes / Q000378:metabolism* / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017480:Receptors, sigma; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010616:Phenanthrenes; D010880:Piperidines; D011804:Quinolines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid; D017480:Receptors, sigma; C046064:HW 165