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

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-HT_1A, 5-HT_2A, 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-HT_1AK_i = 41.5 nM, 5-HT_2AK_i = 315 nM, 5-HT₇K_i = 42.5 nM, D₂K_i = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT_1AK_i = 23.9 nM, 5-HT_2AK_i = 39.4 nM, 5-HT₇K_i = 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.