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

Authors :
Margherita Mastromarino
Mauro Niso
Carmen Abate
Ewgenij Proschak
Mariam Dubiel
Holger Stark
Marián Castro
Enza Lacivita
Marcello Leopoldo
Source :
Molecules, Vol 27, Iss 4, p 1297 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

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-HT1AKi = 41.5 nM, 5-HT2AKi = 315 nM, 5-HT7Ki = 42.5 nM, D2Ki = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT1AKi = 23.9 nM, 5-HT2AKi = 39.4 nM, 5-HT7Ki = 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.

Details

Language :
English
ISSN :
14203049
Volume :
27
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.03fb4ce8fd04f57bd7789c1a958706f
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules27041297