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Papers of the Week


Papers: 25 Feb 2023 - 3 Mar 2023

RESEARCH TYPE:
Review


Pharmacology/Drug Development


2023 Mar 01


J Med Chem


36856340

Multitargeted Opioid Ligand Discovery as a Strategy to Retain Analgesia and Reduce Opioid-Related Adverse Effects.

Authors

Smith MT, Kong D, Kuo A, Imam MZ, Williams CM

Abstract

The global “opioid crisis” has placed enormous pressure on the opioid ligand discovery community to produce novel opioid analgesics with superior opioid-related adverse-effect profiles compared with morphine. In this Perspective, the multitargeted opioid ligand strategy for the discovery of opioid analgesics with superior preclinical therapeutic indices relative to morphine is reviewed and discussed. Dual-targeted μ-opioid (MOP)/δ-opioid (DOP) ligands in which the DOP antagonist potency at least equals that of the MOP agonist activity, and are devoid of DOP or κ-opioid (KOP) agonist activity, are sufficiently promising candidates to warrant further investigation. Dual-targeted MOP/NOP partial agonists have superior preclinical therapeutic indices to morphine and/or fentanyl in nonhuman primates and are also considered promising. Based on the poor preclinical and clinical therapeutic indices of cebranopadol, which is a full agonist at MOP, DOP, and NOP receptors and a partial agonist at the KOP receptor, this pharmacologic template should be avoided.