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., …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 (ACS)
• 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