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Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited (2024)
Journal Article
Underwood, O., Fritzwanker, S., Glenn, J., Blum, N. K., Batista-Gondin, A., Drube, J., Hoffmann, C., Briddon, S. J., Schulz, S., & Canals, M. (2024). Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited. Communications Biology, 7, Article 933. https://doi.org/10.1038/s42003-024-06571-1

Desensitisation of the mu-opioid receptor (MOR) is proposed to underlie the initiation of opioid analgesic tolerance and previous work has shown that agonist-induced phosphorylation of the MOR C-tail contributes to this desensitisation. Moreover, pho... Read More about Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited.

Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans (2024)
Journal Article
Moore, J. C., Modell, L., Glenn, J. R., Jones, K. D., Argent, S. P., Lane, J. R., …Lam, H. W. (2024). Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans. Chemical Communications, 60(47), 6007-6010. https://doi.org/10.1039/d4cc01788a

The enantioselective de novo synthesis of pharmacologically important 14-hydroxy-6-oxomorphinans is described. 4,5-Desoxynaltrexone and 4,5-desoxynaloxone were prepared using this route and their biological activities against the opioid receptors wer... Read More about Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans.

Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity (2023)
Journal Article
Kirchhofer, S. B., Lim, V. J. Y., Ernst, S., Karsai, N., Julia, R. G., Canals, M., …Bünemann, M. (2023). Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity. eLife, 12, Article e91291. https://doi.org/10.7554/eLife.91291

The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activatio... Read More about Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice (2023)
Journal Article
Hill, R., Sanchez, J., Lemel, L., Antonijevic, M., Hosking, Y., Mistry, S. N., …Canals, M. (2023). Assessment of the potential of novel and classical opioids to induce respiratory depression in mice. British Journal of Pharmacology, 180(24), 3160-3174. https://doi.org/10.1111/bph.16199

Background and Purpose
Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respira... Read More about Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics (2023)
Journal Article
Bonifazi, A., Saab, E., Sanchez, J., Nazarova, A. L., Zaidi, S. A., Jahan, K., …Newman, A. H. (2023). Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics. Journal of Medicinal Chemistry, 66(15), 10304–10341. https://doi.org/10.1021/acs.jmedchem.3c00417

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D3 receptor (D3R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity... Read More about Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.

Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders (2021)
Journal Article
DiCello, J. J., Carbone, S. E., Saito, A., Pham, V., Szymaszkiewicz, A., Gondin, A. B., …Poole, D. P. (2022). Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders. AJP - Gastrointestinal and Liver Physiology, 322(1), G66-G78. https://doi.org/10.1152/AJPGI.00297.2021

Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the... Read More about Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders.

Atypical opioid receptors: unconventional biology and therapeutic opportunities (2021)
Journal Article
Palmer, C. B., Meyrath, M., Canals, M., Kostenis, E., Chevigné, A., & Szpakowska, M. (2022). Atypical opioid receptors: unconventional biology and therapeutic opportunities. Pharmacology and Therapeutics, Article 108014. https://doi.org/10.1016/j.pharmthera.2021.108014

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating four opioid receptors, namely μ (mu, MOP), δ (delta, DOP), κ (kappa, KOP) and the nociceptin/orphanin FQ receptor (NOP). Interestingly, several o... Read More about Atypical opioid receptors: unconventional biology and therapeutic opportunities.

Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management (2021)
Journal Article
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

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 dopami... Read More about Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management.

Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14 (2021)
Journal Article
Wang, S., Foster, S. R., Sanchez, J., Corcilius, L., Larance, M., Canals, M., …Payne, R. J. (2021). Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14. ACS Chemical Biology, 16(6), 973-981. https://doi.org/10.1021/acschembio.1c00006

Chemokines are secreted proteins that regulate leukocyte migration during inflammatory responses by signaling through chemokine receptors. Full length CC chemokine ligand 14, CCL14(1–74), is a weak agonist for the chemokine receptor CCR1, but its act... Read More about Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14.

Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10 (2021)
Journal Article
Lim, H. D., Robert Lane, J., Canals, M., & Stone, M. J. (2021). Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10. International Journal of Molecular Sciences, 22(8), Article 4232. https://doi.org/10.3390/ijms22084232

Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the... Read More about Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10.

New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling (2021)
Journal Article
Mann, A., Keen, A. C., Mark, H., Dasgupta, P., Javitch, J. A., Canals, M., …Robert Lane, J. (2022). New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling. Scientific Reports, 11(1), Article 8288. https://doi.org/10.1038/s41598-021-87417-2

The dopamine D2 receptor (D2R) is the target of drugs used to treat the symptoms of Parkinson’s disease and schizophrenia. The D2R is regulated through its interaction with and phosphorylation by G protein receptor kinases (GRKs) and interaction with... Read More about New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling.

A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes (2021)
Journal Article
Mai, Q. N., Shenoy, P., Quach, T., Retamal, J. S., Gondin, A. B., Yeatman, H. R., …Veldhuis, N. A. (2021). A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes. Journal of Biological Chemistry, 296, Article 100345. https://doi.org/10.1016/J.JBC.2021.100345

G-protein-coupled receptors (GPCRs) are traditionally known for signaling at the plasma membrane, but they can also signal from endosomes after internalization to control important pathophysiological processes. In spinal neurons, sustained endosomal... Read More about A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes.

The life cycle of the Mu-Opioid Receptor (2020)
Journal Article
Cuitavi, J., Hipólito, L., & Canals, M. (2021). The life cycle of the Mu-Opioid Receptor. Trends in Biochemical Sciences, 46(4), 315-328. https://doi.org/10.1016/j.tibs.2020.10.002

Opioid receptors are undisputed targets for the treatment of pain. Unfortunately, targeting these receptors therapeutically poses significant challenges including addiction, dependence, tolerance and the appearance of side-effects such as respiratory... Read More about The life cycle of the Mu-Opioid Receptor.

Critical assessment of G protein-biased agonism at the µ opioid receptor (2020)
Journal Article
Gillis, A., Kliewer, A., Kelly, E., Henderson, G., Christie, M. J., Schulz, S., & Canals, M. (2020). Critical assessment of G protein-biased agonism at the µ opioid receptor. Trends in Pharmacological Sciences, 41(12), 947-959. https://doi.org/10.1016/j.tips.2020.09.009

G protein-biased agonists of the µ-opioid receptor have been proposed to be an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the β-arrestin2 knockout mouse that led to this proposal, and... Read More about Critical assessment of G protein-biased agonism at the µ opioid receptor.

Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain (2020)
Journal Article
Jimenez-Vargas, N. N., Gong, J., Wisdom, M. J., Jensen, D. D., Latorre, R., Hegron, A., Teng, S., DiCello, J. J., Rajasekhar, P., Veldhuis, N. A., Carbone, S. E., Yu, Y., Lopez-Lopez, C., Jaramillo-Polanco, J., Canals, M., Reed, D. E., Lomax, A. E., Schmidt, B. L., Leong, K. W., Vanner, S. J., …Poole, D. P. (2020). Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain. Proceedings of the National Academy of Sciences, 117(26), 15281-15292. https://doi.org/10.1073/pnas.2000500117

Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate -opioid receptors (DOPr) in endosomes of noc... Read More about Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain.

Phosphoproteomic characterization of the signaling network resulting from activation of chemokine receptor CCR2 (2020)
Journal Article
Huang, C., Foster, S. R., Shah, A. D., Kleifeld, O., Canals, M., Schittenhelm, R. B., & Stone, M. J. (2020). Phosphoproteomic characterization of the signaling network resulting from activation of chemokine receptor CCR2. Journal of Biological Chemistry, 295, 6518-6531. https://doi.org/10.1074/jbc.ra119.012026

Leukocyte recruitment is a universal feature of tissue inflammation and regulated by the interactions of chemokines with their G protein-coupled receptors (GPCRs). Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, includi... Read More about Phosphoproteomic characterization of the signaling network resulting from activation of chemokine receptor CCR2.

Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists (2020)
Journal Article
Gillis, A., Gondin, A. B., Kliewer, A., Sanchez, J., Lim, H. D., Alamein, C., …Canals, M. (2020). Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists. Science Signaling, 13(625), Article eaaz3140. https://doi.org/10.1126/scisignal.aaz3140

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of... Read More about Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists.

A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor (2019)
Journal Article
Dekan, Z., Sianati, S., Yousuf, A., Sutcliffe, K. J., Gillis, A., Mallet, C., …Christie, M. J. (2019). A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor. Proceedings of the National Academy of Sciences, 116(44), 22353-22358. https://doi.org/10.1073/pnas.1908662116

An Australian estuarine isolate ofPenicilliumsp. MST-MF667 yielded3 tetrapeptides named the bilaids with an unusual alternating LDLDchirality. Given their resemblance to known short peptide opioidagonists, we elucidated that they were weak (Kilow mic... Read More about A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor.

Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks (2019)
Journal Article
Civciristov, S., Huang, C., Liu, B., Marquez, E. A., Gondin, A. B., Schittenhelm, R. B., …Halls, M. L. (2019). Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks. Journal of Biological Chemistry, 294(44), 16198-16213. https://doi.org/10.1074/jbc.ra119.008685

Ligand-dependent differences in the regulation and internalization of the mu-opioid receptor (MOR) have been linked to the severity of adverse effects that limit opiate use in pain management. MOR activation by morphine or [D-Ala2,N-MePhe4,Gly-ol]-en... Read More about Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks.