Structure-Based SAR in the Design of Selective or Bifunctional Nociceptin (NOP) Receptor Agonists

The nociceptin opioid receptor (NOP), the fourth member of family, and its endogenous peptide ligand, or orphanin FQ (N/OFQ), play a vital role in several central nervous system pathways regulating pain, reward, feeding, anxiety, motor control learning/memory. Both selective NOP agonists as well bifunctional at mu (MOP) have potential therapeutic applications CNS disorders related to these processes. Using Surflex-Dock protocols, we conducted computational structure-activity study four scaffold classes ligands with varying NOP-MOP selectivity. By docking compounds into orthosteric binding sites within an active-state homology model, MOP crystal structure, goal this was use structure-based drug design approach modulate affinity vs. We first docked parent (no side chain) determine their interactions pockets. Various polar sidechains were added heterocyclic A-pharmacophore ligand affinity. substitutions mainly contained 1-2 carbon chain substituent such amine, alcohol, sulfamide, guanidine. SAR analysis is focused on impact structural changes sidechain, length, hydrogen bonding capability, basic vs neutral functional groups selectivity both receptors. This highlights modifications that can be leveraged rationally different ratios efficacy.