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Based on a mu opioid receptor (MOR) homology model and the “isosterism” concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR selective ligands. The first generation ligands appeared to be MOR selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a non-conserved residue facilitated “hydrogen bonding network” that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual selective ligand 10 showed no agonism and acted as a potent antagonist in the tail flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual selective ligands, which might possess unique therapeutic value for opioid addiction treatment.
Yuan et al. (Mon,) studied this question.