Investigating the Landscape of C6-Azaindole Side Chain on the Epoxymorphinan Skeleton via the Nitrogen Walk Concept: A Strategy to Enhance Drug-Like Properties

Opioid use disorder (OUD) affects 2.1 million people in the U.S., and current treatments have significant limitations. Therefore, there is a critical need for novel, selective, potent, and reversible mu opioid receptor (MOR) antagonists for OUD treatment. The "message-address" concept applied to the naltrexone skeleton keeps the epoxymorphinan core (message) consistent while modifying the C-6 substituent (address). This approach led to the development of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (<b>NAN</b>). In this study, we have designed and evaluated <b>NAN</b> analogues to enhance their pharmacological properties by applying the "nitrogen-walk" concept, i.e., replacing each CH group with a nitrogen atom on the indole ring sequentially while exploring different attachment positions onto the azaindole ring. A total of 36 analogues were synthesized and characterized. Competitive binding assays and functional activity studies identified eight potential MOR antagonists, with compound <b>7</b> showing the highest potency in a mouse antinociception model and inducing fewer withdrawal symptoms than naloxone.