- Novel Dual-Target μ-Opioid Receptor and Dopamine D3Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management
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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.
- 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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p. 7778 - 7808
(2021/06/27)
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- Molecular determinants of selectivity and efficacy at the dopamine D3 receptor
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The dopamine D3 receptor (D3R) has been implicated in substance abuse and other neuropsychiatric disorders. The high sequence homology between the D3R and D2R, especially within the orthosteric binding site (OBS) that binds dopamine, has made the developm
- Newman, Amy Hauck,Beuming, Thijs,Banala, Ashwini K.,Donthamsetti, Prashant,Pongetti, Katherine,Labounty, Alex,Levy, Benjamin,Cao, Jianjing,Michino, Mayako,Luedtke, Robert R.,Javitch, Jonathan A.,Shi, Lei
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experimental part
p. 6689 - 6699
(2012/09/25)
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- MEDICAMENTS
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A compound of formula (I) is described: wherein R1 and R2 are as defined in the text and wherein the compounds are intended for use in treating medical conditions characterized by an imbalance in dopamine receptor activity.
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Page/Page column 94
(2009/06/27)
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