Synthesis, Pharmacological Characterization and QSAR Modelling of 4-Phenylpiperidines and 4-Phenylpiperazines Effects on the dopaminergic neurotransmission in vivo

Abstract: The endogenous neurotransmitter dopamine (DA) is involved in several functions that are controlled from the central nervous system (CNS), for example behaviour, memory, cognition and reward. A disturbed dopaminergic neurotransmission may lead to many severe conditions, such as schizophrenia, attention deficit hyperactivity disorder (ADHD) or Parkinson's disease (PD). The dopamine receptors belong to the G-protein coupled receptors (GPCRs) and are divided into five distinct subtypes (D1-D5). These subtypes can be either of the D1- or D2-types based on their effect on the production of cyclic adenosine monophosphate (cAMP). The most common dopaminergic receptor used as target for pharmaceuticals is by far the D2 receptor and drugs acting as full agonists, partial agonists and antagonists at this receptor have been developed. In the search for new dopaminergic ligands, a set of 4-phenylpiperidines and 4-phenylpiperazines have been synthesized and their effects have been tested in both in vivo and in vitro assays. Starting with the known partial agonist 3-(1-benzylpiperidin-4-yl)phenol, stepwise structural modifications of functional groups afforded mainly D2 antagonists but with a conserved preference for binding to the agonist binding site and fast dissociation rates from the receptor. However, further modifications, including changes of the position of the aromatic substituent, indicated that other targets than the D2 receptor was involved and binding affinity studies later concluded that some of these compounds had MAO A inhibiting properties. In order to fully elucidate what structural properties are related to the different pharmacological responses, QSAR models with physicochemical descriptors set against each respective response were acquired by means of partial least square (PLS) regression. Models with high predictivity (Q2>0.53) were obtained and the interpretation of these models has provided an improved understanding of how structural modifications in this chemical class affect the response both in vivo and in vitro. The structural motifs that were investigated included the position and physicochemical properties of the aromatic substituent as well as the heterocycle being a piperazine or a piperidine. All these properties turned out to be significant for the different responses in some aspect. In addition, a strong correlation between the affinities to the D2 receptor and to MAO A and the levels of the metabolite DOPAC in striatum has been established. This led us to the conclusion that it is primarily interactions with these two targets that lead to the in vivo response observed for this class of compounds.