Application of Bivalent Bioisostere Concept on Design and Discovery of Potent Opioid Receptor Modulators.

Here, we described the structural modification of previously identified μ opioid receptor (MOR) antagonist NAN, a 6α--7'-indolyl substituted naltrexamine derivative, and its 6β--2'-indolyl substituted analogue INTA by adopting the concept of "bivalent bioisostere". Three newly prepared opioid ligands, (NBF), , and , were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the "address" portions of them may have negative or positive allosteric modulation effects on the function of their "message" portions compared with NAN and INTA. Collectively, our successful application of the "bivalent bioisostere concept" identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.