Synthesis and Pharmacology of a Novel μ–δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template

Faouzi, Abdelfattah; Uprety, Rajendra; Gomes, Ivone; Massaly, Nicolas; Keresztes, Attila; Rouzic, Valerie Le; Gupta, Achla; Zhang, Tiffany; Yoon, Hye Jean; Ansonoff, Michael; Allaoa, Abdullah; Pan, Ying Xian; Pintar, John E.; Morón, José A.; Streicher, John M.; Devi, Lakshmi A.; Majumdar, Susruta

doi:10.1021/acs.jmedchem.0c00901

Cited by 27 publications

(18 citation statements)

References 70 publications

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“…This leaves open the potential for false-positive and negative results because of the indirect analysis. Future studies should use MDOR-selective agonists such as MP135 11 to directly confirm and extend these findings. Another limitation is that our phosphosite enrichment method may introduce potential biases by phosphosite, peptide length, and other chemical features which may enrich some peptides over others.…”

Section: Discussionmentioning

confidence: 81%

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Keresztes

Olson

Nguyen

et al. 2021

Pain

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The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus cotreated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone antinociception in all models by 54.7% to 628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism, we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced antinociception using small molecule inhibitors (KN93 and Src-I1). Together, these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs through the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.

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Section: Discussionmentioning

confidence: 81%

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Keresztes

Olson

Nguyen

et al. 2021

Pain

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“…Over the last ~15 years, the discovery of G protein biased opioid ligands has been widely considered as a strategy for the development of potent but safer opioid analgesics. In spite of TRV130’s clinical approval, the results pointing to the ability of MOR-specific G protein biased ligands to alleviate opioid side effects has recently been challenged ( Kliewer et al, 2019 ; Hill et al, 2018 ; Faouzi et al, 2020b ). Among the most important recent findings is that the respiratory depressant effects of morphine appear to be β -arrestin 2-independent.…”

Section: Discussionmentioning

confidence: 99%

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Uprety

Che

Zaidi

et al. 2021

eLife

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Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

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“…The dimerisation of opioid receptors has been shown to influence receptor trafficking, signalling and the ability to inhibit or delay tolerance and dependence/addiction [3][4][5]. With regards to heterodimeric pairings, the majority of work in this field has been based on the association between MOP and delta opioid peptide (DOP) receptors [6][7][8][9][10][11][12][13]. There is growing evidence to suggest that the potential pairing of the MOP and nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor systems may be beneficial in developing analgesics with reduced side effects [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

et al. 2022

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Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.

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Synthesis and Pharmacology of a Novel μ–δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template

Cited by 27 publications

References 70 publications

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

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