ON THE QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS OF META-SUBSTITUTED (S)-PHENYLPIPERIDINES, A CLASS OF PREFERENTIAL DOPAMINE D-2 AUTORECEPTOR LIGANDS - MODELING OF DOPAMINE SYNTHESIS AND RELEASE IN-VIVO BYMEANS OF PARTIAL LEAST-SQUARES REGRESSION

The quantitative structure-activity relationship between physicochemic al properties and effects on dopamine (DA) synthesis and release in th e rat brain, in a series of meta-substituted (S)-phenylpiperidines, ha s been investigated by means of partial least squares regression (PLS) . The effect on DA synthesis caused by the drugs, in both non-pretreat ed and reserpine-pretreated rats, was assessed by measurements of tiss ue levels of L-DOPA accumulated in the striatum following treatment wi th a decarboxylase inhibitor. Assessment of effects on DA release was performed by analysis of perfusates collected from implanted microdial ysis probes. The numerical characterization of the variation in physic ochemical features of the phenylpiperidines used in the regression mod eling was accomplished by using common tabulated aromatic and aliphati c substituent constants in combination with a set of property descript ors derived from molecular mechanics and semiempirical calculations. I t was found that the biochemical responses could be accurately predict ed by the regression models based on these molecular feature measures. The molecular features exerting influence on DA synthesis were found to be markedly different from those influencing DA release. This findi ng is discussed in terms of the possible existence of a dopamine recep tor-mediated DA release-controlling mechanism, which may not involve t he synthesis regulating DA D-2 autoreceptor. Some findings regarding t he impact of the piperidine N substituent on agonist properties of the drugs are reported. The regression models were also used for guidance in the search for a phenylpiperidine with a lower intrinsic activity, at the DA D-2 type autoreceptor, than the partial DA agonist preclamo l (3).