Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists

Abstract

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT₂ receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT_2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both G_q-mediated calcium flux and β-arrestin recruitment assays, which revealed that these compounds exhibited no β-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward G_q signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT_2C signaling pathways and the development of alternative antipsychotic medications.

Keywords: 5-HT(2C) receptor agonist; Antipsychotic; Aporphine; Functional selectivity; G protein-biased; Serotonin; β-arrestin recruitment.