Novel dual kappa/mu opioid ligands based on a tetrahydroisoquinoline-valine hybrid nucleus

Opioid addiction constitutes a significant global health challenge. Kappa opioid receptor (KOP) modulators have demonstrated efficacy in treating resistant drug abuse cases. However, till date, no selective KOP antagonists have successfully reached the market. In this study, we employed structure-based design to modify JDTic, the most potent KOP antagonist, into a series of novel analogs based on a tetrahydroisoquinoline (THIQ)-valine hybrid scaffold. More than 20 compounds were synthesized and assessed for binding affinities to the three opioid receptor subtypes. Ten derivatives showed a binding Ki of less than 10 µM for KOP. Subsequent functional characterization using [³⁵S]GTP-γ-S and in vivo animal models established that most of these analogs possess mixed agonist and antagonist properties for both kappa and mu opioid receptors. For example, compound (R)-10m exhibited agonist activity for KOP and MOP receptors, with IC₅₀ values of 670 and 94.5 nM, respectively. Subsequent testing indicated that (R)-10m possesses an analgesic profile with a comparable latency to the positive control, Nalbuphine, in the tail-flick animal model, while compound (S)-10h was found to be a sub-micromolar KOP/MOP antagonist. These results suggest that incorporating relatively bulky and hydrophobic appendages to the privileged THIQ-valine scaffold is necessary to retain and fine-tune the affinity and selectivity for KOP.