Alessandro Bonifazi
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
Authors
Francisco O. Battiti
JULIE SANCHEZ JULIE.SANCHEZ@NOTTINGHAM.AC.UK
Research Fellow - Pharmacology Cell Biologist
Saheem A. Zaidi
Eric Bow
Mariia Makarova
Jianjing Cao
Anver Basha Shaik
Agnieszka Sulima
Kenner C. Rice
Vsevolod Katritch
MERITXELL CANALS M.CANALS@NOTTINGHAM.AC.UK
Professor of Cellular Pharmacology
J. Robert Lane
Amy Hauck Newman
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 |
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