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, 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.

OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including G?z (2022)
Journal Article
Keen, A. C., Pedersen, M. H., Lemel, L., Scott, D. J., Canals, M., Littler, D. R., …Lane, J. R. (2022). OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz. Communications Biology, 5(1), Article 256. https://doi.org/10.1038/s42003-022-03191-5

Heterotrimeric G proteins are the main signalling effectors for G protein-coupled receptors. Understanding the distinct functions of different G proteins is key to understanding how their signalling modulates physiological responses. Pertussis toxin,... Read More about OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including G?z.

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine (2022)
Journal Article
Hill, R., Kruegel, A. C., Javitch, J. A., Lane, J. R., & Canals, M. (2022). The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine. British Journal of Pharmacology, 179(14), 3875-3885. https://doi.org/10.1111/bph.15832

Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious μ receptor agon... Read More about The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine.

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.

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia (2021)
Journal Article
Lillywhite, A., Woodhams, S. G., Gonçalves, S. V., Watson, D. J. G., Li, L., Burston, J. J., …Chapman, V. (2021). Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia. PAIN Reports, 6(4), Article e956. https://doi.org/10.1097/PR9.0000000000000956

Introduction: Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises.... Read More about Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia.

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.

Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology (2021)
Journal Article
Hill, R., & Canals, M. (2022). Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology. Pharmacology and Therapeutics, 230, Article 107961. https://doi.org/10.1016/j.pharmthera.2021.107961

Morphine and other mu-opioid receptor (MOR) agonists remain the mainstay treatment of acute and prolonged pain states worldwide. The major limiting factor for continued use of these current opioids is the high incidence of side effects that result in... Read More about Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology.

Novel Dual-Target ?-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 ?-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.