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Papers of the Week

Papers: 15 May 2021 - 21 May 2021

Pharmacology/Drug Development

2021 May 20

J Med Chem

Novel Dual-Target μ-Opioid Receptor and Dopamine D Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management.


Bonifazi A, Battiti FO, Sanchez J, Zaidi SA, Bow E, Makarova M, Cao J, Shaik A B, Sulima A, Rice KC, Katritch V, Canals M, Lane RJ, Newman A H
J Med Chem. 2021 May 20.
PMID: 34011153.


The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D receptor (DR) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the DR as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and DR. Structure-activity relationship studies using computationally aided drug design and binding assays led to the identification of potent dual-target leads (, , and ), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-DR antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.