Discovery, SAR, and molecular basis of...

Opioid analgesics remain a cornerstone of pain management, among which μ-opioid receptor (MOR) agonists dominate clinical practice due to their well-established efficacy. However, dose related adverse effects (e.g., respiratory depression, addiction potential) constrain their therapeutic utility, driving sustained efforts to develop novel MOR agonists with improved safety profiles. Building upon our previously identified lead compound FWB2, a series of 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)piperidin-4-ol derivatives was designed via structure-based drug design (SBDD), synthesized, and systematically evaluated through comprehensive in vitro and in vivo pharmacological profiling. Systematic structure-activity relationship (SAR) exploration identified (R, (3R,4S))-6c as a novel and selective MOR agonist (MOR K_i = 0.9 nM, MOR: DOR: KOR = 1: 561.1: 188.3; MOR EC₅₀ = 89.9 nM), demonstrating potent antinociceptive activity (ED₅₀ = 1.63 mg/kg) in the hot plate model. Molecular docking studies elucidated the binding mode of (R,(3R,4S))-6c with the MOR, identifying its molecular interactions with four critical residues W318^7.35, D147^3.32, H54 and W293^6.48, while delineating the structural features of the ligand-receptor binding pocket.