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

ABSTRACT: 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 antag

SUBMITTER: Abdelwaly A 

PROVIDER: S-EPMC12533025 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature