Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management
| Autor: | Saheem A. Zaidi, Julie Sanchez, Meritxell Canals, Alessandro Bonifazi, Eric Bow, Mariia Makarova, Kenner C. Rice, Agnieszka Sulima, Jianjing Cao, Amy Hauck Newman, J. Robert Lane, Vsevolod Katritch, Anver Basha Shaik, Francisco O. Battiti |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
medicine.drug_class Chemistry Antagonist Pharmacology 01 natural sciences Partial agonist 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Opioid Opioid receptor Dopamine receptor D3 Drug Discovery medicine Molecular Medicine Structure–activity relationship Binding site Receptor 030304 developmental biology medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 64:7778-7808 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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