Novel Dual-Target Mu Opioid (MOR) and Dopamine D(3) Receptors (D(3)R) Ligands as Potential Non-Addictive Pharmacotherapeutics for Pain Management
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Binding Sites
Biphenyl Compounds Receptors Dopamine D3 Receptors Opioid mu Pain Ligands Opioid-Related Disorders Article Analgesics Opioid Molecular Docking Simulation Disease Models Animal Mice Structure-Activity Relationship Drug Design Fluorescence Resonance Energy Transfer Animals Dopamine Antagonists Pain Management |
| Zdroj: | J Med Chem |
| 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 dopamine D(3) receptors (D(3)R) 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 D(3)R 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 MOR and D(3)R. 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. BRET-based functional studies revealed MOR agonist-D(3)R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability. |
| Databáze: | OpenAIRE |
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