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

Bonifazi, Alessandro; Battiti, Francisco O.; Sanchez, Julie; Zaidi, Saheem A.; Bow, Eric; Makarova, Mariia; Cao, Jianjing; Shaik, Anver Basha; Sulima, Agnieszka; Rice, Kenner C.; Katritch, Vsevolod; Canals, Meritxell; Lane, J. Robert; Newman, Amy Hauck

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.

Citation

Bonifazi, A., Battiti, F. O., Sanchez, J., Zaidi, S. A., Bow, E., Makarova, M., Cao, J., Shaik, A. B., Sulima, A., Rice, K. C., Katritch, V., Canals, M., Lane, J. R., & Newman, A. H. (2021). Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management. Journal of Medicinal Chemistry, 64(11), 7778-7808. https://doi.org/10.1021/acs.jmedchem.1c00611

• Journal Article Type: Article
• Acceptance Date: May 5, 2021
• Online Publication Date: May 20, 2021
• Publication Date: May 20, 2021
• Deposit Date: Nov 19, 2021
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 64
• Issue: 11
• Pages: 7778-7808
• DOI: https://doi.org/10.1021/acs.jmedchem.1c00611
• Keywords: Molecular Medicine; Drug Discovery
• Public URL: https://nottingham-repository.worktribe.com/output/5633799
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00611