Design, Synthesis, and Biological Evaluation of Mu Opioid Receptor Selective Antagonists Bearing Pyrazole and Imidazole Side Chains

Opioid Use Disorder (OUD) is one of the major national threats to human health and economic system. Since the opiate substances produce their pharmacological effects mainly at the Mu Opioid Receptor (MOR), the development of potent MOR selective antagonists is imperative. By application of the message-address concept, the novel selective MOR antagonist, NAP was synthesized in our group. The molecular modeling studies of NAP revealed that its MOR selectivity was determined by interactions between the C(6) side chain and the non-conserved residues of the receptor. To enrich our understanding of Structure-Activity Relationship (SAR) of the opioid ligands as well as diversify and enlarge our opioid ligand library, we modified the NAP structure at C(6) position by replacing the pyridine ring with the pyrazole and imidazole moieties, varying the configuration, and introducing the spacer between the epoxymorphinan skeleton and the aromatic ring. Here, sixteen compounds bearing pyrazole and imidazole side chains were designed, synthesized, and biological evaluated. The in vitro radioligand binding and [35S]-GTPγS functional assays demonstrated that compounds 6, 11, and 14 showed MOR binding affinity, potency, and % relative efficacy comparable to those of naltrexone and NAP, suggesting their potential to be the MOR antagonists. This observation was supported by the results from the preliminary in vivo warm-water tail immersion assay (agonism study), which compounds 6, 11, and 14 showed mild antinociceptive effects. The molecular modeling studies also showed the interactions between the address moieties of these compounds and the non-conserved amino acid residues in the MOR binding pocket which might facilitate their binding selectivity and antagonism effect. Overall, this research could enlarge the opioid ligand library and aid in enhancing a comprehensive understanding of opioid ligand SAR for further rational design and structural modification of a lead compound to develop novel potent MOR selective antagonist for treating opioid addiction