Design, synthesis, and biological activity of novel para-substituted phenylamino and phenyl derivatives of northebaine as selective delta opioid receptor agonists

The delta opioid receptor (DOR) is a promising target for developing analgesics with fewer side effects compared to mu opioid receptor (MOR) agonists. However, non-peptidyl DOR-selective agonists remain limited. Using the “message-address” concept in opioid ligand design, we designed and synthesized a series of para-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoetheno-tetrahydronorthebaines to explore their binding affinity and selectivity for DOR over MOR and kappa opioid receptor (KOR). Key findings revealed that para-substituted phenylamino derivatives exhibited high DOR affinity and subtype selectivity. Functional assays confirmed their agonistic activity at DOR, with compounds 4a and 4e showing IC₅₀ values of 580.9 nM and 4807 nM, respectively. Molecular modeling studies revealed that DOR selectivity might be mediated by specific interactions with residue L300^7.35 in the TM7 domain, where structural rearrangement of the address component facilitates its transition from KOR- to DOR-selective binding modes. These findings highlight the critical role of “address” component optimization in achieving receptor subtype specificity, providing a structure-based strategy for developing new opioid therapeutics with tailored pharmacological profiles.