Design and Synthesis of Arylpiperazine Serotonergic/Dopaminergic Ligands with Neuroprotective Properties.

Margherita Mastromarino,Marián Castro,Enza Lacivita,Carmen Abate,Holger Stark,Mariam Dubiel,Mauro Niso,Marcello Leopoldo,Ewgenij Proschak

doi:10.3390/molecules27041297

Abstract

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT1A, 5-HT2A, 5-HT7 receptor, and dopamine D2 receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood–brain barrier. We identified compound 12a that combines an affinity profile compatible with antipsychotic activity (5-HT1A Ki = 41.5 nM, 5-HT2A Ki = 315 nM, 5-HT7 Ki = 42.5 nM, D2 Ki = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT1A Ki = 23.9 nM, 5-HT2A Ki = 39.4 nM, 5-HT7 Ki = 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound 9b, which might be suitable for studies in vivo.

Highlights

The long-chain arylpiperazine structure is a versatile model that has allowed the identification of several drugs over the years, such as antipsychotics [1], anxiolytics [2], and antiparkinsonian drugs [3] (Figure 1)
The above-mentioned drugs owe their action to the modulation at the central nervous system (CNS) level of one or more serotonin and/or dopamine receptors that are relevant to the specific pathology
The anxiolytic action of buspirone is due to a partial agonist activity on the 5-HT1A receptors, while the antiparkinsonian effect of piribedil is due to dopaminergic D2 receptors activation

Summary

Introduction

The long-chain arylpiperazine structure is a versatile model that has allowed the identification of several drugs over the years, such as antipsychotics (aripiprazole, ziprasidone, and lurasidone) [1], anxiolytics (buspirone, tandospirone) [2], and antiparkinsonian drugs (piribedil) [3] (Figure 1). This variety of actions is due to the possibility of modulating the pharmacological profile of the arylpiperazine derivatives through structural variations. Aripiprazole owes its antipsychotic action to the blocking of dopaminergic D2 and serotonergic 5-HT2A receptors. The anxiolytic action of buspirone is due to a partial agonist activity on the 5-HT1A receptors, while the antiparkinsonian effect of piribedil is due to dopaminergic D2 receptors activation

Methods

Results

Discussion

Conclusion