Design, Synthesis, and Evaluation of Novel (−)-cis-N-Normetazocine Derivatives: In Vitro and Molecular Modeling Insights

Suitable structural modifications of the functional groups at N-substituent of (−)-cis-N-normetazocine nucleus modulate the affinity and activity profile of related ligands toward opioid receptors. Our research group has developed several compounds and the most interesting ligands, LP1 and LP2, exhibited a dual-target profile for mu-opioid receptor (MOR) and delta-opioid receptor (DOR). Recent structure–affinity relationship studies led to the discovery of novel LP2 analogs (compounds 1 and 2), which demonstrated high MOR affinity in the nanomolar range. Here, we reported the synthesis of the new (−)-cis-N-normetazocine derivatives (3–8) characterized by the absence of the phenyl ring in the N-substituent compared to all previous reported ligands. Compounds 3 and 4, featuring a methyl ester functional group in the N-substituent, retained significant MOR affinity and exhibited similar affinity for the kappa-opioid receptor (KOR). In contrast, compounds 7 and 8, which contain a hydroxamic acid functionality, maintained affinity exclusively toward MOR. Neither of compounds (3–8) showed DOR affinity. Molecular modeling studies confirmed a similar docking pose in the MOR binding pocket for these compounds. Additionally, the in silico ADME profile of the most interesting ligands (3, 4, 7, and 8) was investigated revealing a favorable profile for compound 7 regarding the blood–brain barrier permeability, suggesting its potential as a peripherally restricted opioid ligand.