Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management.

Abstract

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 D3 receptor (D3R) 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 D3R 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 D3R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), 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-D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.

• Authors: Alessandro Bonifazi, Francisco O Battiti, Julie Sanchez, Saheem A Zaidi, Eric Bow, Mariia Makarova, Jianjing Cao, Anver Basha Shaik, Agnieszka Sulima, Kenner C Rice, Vsevolod Katritch, Meritxell Canals, J Robert Lane, Amy Hauck Newman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 11 Pg. 7778-7808 (06 10 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34011153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Analgesics, Opioid
• Biphenyl Compounds
• Dopamine Antagonists
• Ligands
• Receptors, Dopamine D3
• Receptors, Opioid, mu
• diphenyl

Topics

• Analgesics, Opioid (therapeutic use)
• Animals
• Binding Sites
• Biphenyl Compounds (chemistry, metabolism, therapeutic use)
• Disease Models, Animal
• Dopamine Antagonists (chemistry, metabolism, therapeutic use)
• Drug Design
• Fluorescence Resonance Energy Transfer
• Ligands
• Mice
• Molecular Docking Simulation
• Opioid-Related Disorders (drug therapy)
• Pain (drug therapy)
• Pain Management
• Receptors, Dopamine D3 (agonists, antagonists & inhibitors, metabolism)
• Receptors, Opioid, mu (agonists, metabolism)
• Structure-Activity Relationship