On the Quantitative Structure-Activity Relationships of Meta-Substituted (S)-Phenylpiperidines, a Class of Preferential Dopamine D2 Autoreceptor Ligands: Modeling of Dopamine Synthesis and Release in Vivo by Means of Partial Least Squares Regression

Abstract

The quantitative structure-activity relationship between physicochemical properties and effects on dopamine (DA) synthesis and release in the rat brain, in a series of meta-substituted (S)-phenylpiperidines, has been investigated by means of partial least squares regression (PLS). The effect on DA synthesis caused by the drugs, in both non-pretreated and reserpine-pretreated rats, was assessed by measurements of tissue levels of L-DOPA accumulated in the striatum following treatment with a decarboxylase inhibitor. Assessment of effects on DA release was performed by analysis of perfusates collected from implanted microdialysis probes. The numerical characterization of the variation in physicochemical features of the phenylpiperidines used in the regression modeling was accomplished by using common tabulated aromatic and aliphatic substituent constants in combination with a set of property descriptors derived from molecular mechanics and semiempirical calculations. It was found that the biochemical responses could be accurately predicted 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 finding is discussed in terms of the possible existence of a dopamine receptor-mediated DA release-controlling mechanism, which may not involve the synthesis regulating DA D2 autoreceptor. Some findings regarding the 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 D2 type autoreceptor, than the partial DA agonist preclamol (3).