Structure-Affinity Relationship Optimization of SYA16263 Yields New Ligands with Improved Receptor Affinity and...

Central nervous system (CNS) disorders are multifactorial in nature. Dopamine (DA) and serotonin (5-HT) receptors are the prime targets for antipsychotic drug development. In particular, D₂-like (D₂, D₃ and D₄), 5-HT_1A and 5-HT_2A receptors are strongly implicated in the pathophysiology of many neuropsychiatric conditions such as anxiety, schizophrenia, mood and hyperactivity disorders. However, selectivity of the ligands at different receptor subtypes and crosstalk between them complicates the scenario. Development of new ligands that exhibit selectivity toward specific receptor subtypes may aid in understanding their interplay in various CNS disease pathologies. Previously, we reported SYA16263 (6) with high binding affinities toward the D₄ and 5-HT_1A receptors and moderate binding affinities at the D₂, D₃, 5-HT_2A and 5-HT_7A receptors. Further, we have shown that compound 6 exhibits functional selectivity, producing antipsychotic-like effects in rodents without inducing the side effect of catalepsy. In this work, an extended structure-affinity relationship (SAfiR) investigation was carried out with structural modifications at the p-fluorophenyl moiety of 6 by varying the aryl/heteroaryl groups, tweaking the linkage connectivity, and the connecting chain length at the nonpiperazinyl aryl region to improve receptor affinity at D₂R, and 5-HT_1AR. Our SAfiR studies resulted in compounds 35 and 36, with enhanced affinities at D₂R, D₃R, and 5-HT_1AR compared to 6. In addition, compound 35 exhibited improved binding affinity at 5-HT_2AR while compound 36 showed enhancement at 5-HT_7AR. Docking studies were performed with compounds 6, 36 and reference drug, lurasidone to gain structural insight into the ligand-receptor interactions at both the D₂ and 5-HT_2A receptors. Subsequently, pharmacological evaluation of 35 and 36 in the mouse model of schizophrenia using the apomorphine-induced climbing behavior study produced a dose-dependent reduction in climbing behavior and its effects were compared against lurasidone, a standard antipsychotic drug. Further, 35 and 36 did not induce catalepsy in rats even at their respective 3 x 3ED₅₀ doses. Thus, 35 and 36 have the potential to produce antipsychotic-like results in humans in a manner similar to lurasidone. Our future studies are planned to include preclinically evaluating pharmacological responses in specific genetic models to strengthen findings on antipsychotic effects.