Design of a Novel Tricyclic Opioid Scaffold Inspired by Amitriptyline: A Computational Docking Study

The opioid receptor family remains a key target in pain management, yet the discovery of novel scaffolds with favorable CNS penetration and selective μ-opioid activity is limited. Here, we report a tricyclic scaffold inspired by amitriptyline, modified to incorporate opioid pharmacophore features including a phenolic hydroxyl and a tertiary amine side chain. Computational docking of the ligand against the μ-opioid receptor was performed across nine poses, with interactions analyzed using PLIP [4]. The ligand engages a conserved hydrophobic pocket (ILE 245, VAL 249, ILE 271, TRP 242) and forms hydrogen bonds and salt bridges with polar residues (HIS 3, ASP 96, TYR 97/275). Our results suggest that this tricyclic scaffold is compatible with the μ-opioid receptor binding site and may serve as a starting point for further medicinal chemistry optimization.