First Structure-Activity-Relationship Study of Potent G2A Antagonists

G2A inhibition has recently been proposed as a novel therapeutic approach to treat oxaliplatin-induced neuropathic pain (OINP) and breast cancer. However, very few G2A antagonists are known to date. In this study, we report the discovery of a novel series of G2A antagonists developed within our research group, along with the first comprehensive structure–activity relationship (SAR) investigation for this class of compounds. Utilizing a rational design approach, we systematically explored the effects of structural modifications on G2A receptor binding and functional activity. The SAR study identified key molecular features critical for potent G2A inhibition. Two of the newly discovered compounds exhibited submicromolar activity and acceptable selectivity profile among GPCRs.