Synthesis, pharmacological evaluation and QSAR modeling of mono-substituted 4-phenylpiperidines and 4-phenylpiperazines

A series of mono-substituted 4-phenylpiperidines and -piperazines have been synthesized and their effects on the dopaminergic system tested in vivo. The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats. In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression. Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response. These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class.

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► Synthesis of new mono-substituted phenylpiperidines/-piperazines is presented.
► The effect on both DOPAC levels in vivo and DA D2 and MAO A affinity in vitro is investigated.
► The position and physicochemical character of the aromatic substituent are important to the effects.
► QSAR models can describe what structural motifs determine each pharmacological response.
► A strong correlation between the effects in vivo and in vitro is observed.