A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects

Pryce, Kerri D.; Kang, Hye Jin; Sakloth, Farhana; Liu, Yongfeng; Khan, S. A.; Tóth, Katalin; Kapoor, Anoop; Nicolais, Andrew; Che, Tao; Qin, Lianju; Bertherat, Feodora; Kanıskan, H. Ümit; Jin, Jian; Cameron, Michael D.; Roth, Bryan L.; Zachariou, Venetia; Filizola, Marta

doi:10.1016/j.neuropharm.2021.108673

Cited by 25 publications

(10 citation statements)

References 34 publications

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“…Data were fitted according to the Black Leff Ehlert equation using Prism 9.0. In this assay, the binding cooperativity factor, alpha, and efficacy cooperativity factor, beta, provide estimates of the effect of the allosteric modulator on binding and efficacy, respectively, of the orthosteric agonist . These can be expressed together as α*β or composite cooperativity.…”

Section: Resultsmentioning

confidence: 99%

“…In this assay, the binding cooperativity factor, alpha, and efficacy cooperativity factor, beta, provide estimates of the effect of the allosteric modulator on binding and efficacy, respectively, of the orthosteric agonist. 39 These can be expressed together as α*β or composite cooperativity. From our assay, compounds 8−10 are agonists with possibly a small amount of modulation that is difficult to fit and, thus, quantify.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

et al. 2022

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An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates 8–10 featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound 6 in the cAMP GloSensor assays. Radiolabeling of compounds 8 and 9 (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/μmol; and excellent radiochemical purity, >98%. Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [18F]9 in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [18F]6. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [18F]9. As a selective ligand, [18F]9 has the potential to be developed for translational studies.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

et al. 2022

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“…For studies using models of peripheral inflammation, two-to three-month old mice received 30uL left hindpaw injections of Complete Freund’s Adjuvant (CFA; diluted 1:1 in saline), as described ( 106 ). For studies using the post-operative incision model, two- to three-month old mice received an incision from the posterior plantar surface of the hindpaw to the middle of the paw pads, in which dermis and superficial muscle was cut and dermis was sutured afterwards as cited ( 111 ). CFA and paw incision groups of mice received daily intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

Serafini¹,

Frere

Zimering

et al. 2022

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Despite being largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and long-lasting phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster infection model to characterize the effects of SARS-CoV-2 versus Influenza A virus (IAV) infection on the sensory nervous system. Efforts to detect the presence of virus in the cervical/thoracic spinal cord and dorsal root ganglia (DRGs) demonstrated detectable levels of SARS-CoV-2 by quantitative PCR and RNAscope uniquely within the first 24 hours of infection. SARS-CoV-2-infected hamsters demonstrated mechanical hypersensitivity during acute infection; intriguingly, this hypersensitivity was milder, but prolonged when compared to IAV-infected hamsters. RNA sequencing (RNA-seq) of thoracic DRGs from acute infection revealed predominantly neuron-biased signaling perturbations in SARS-CoV-2-infected animals as opposed to type I interferon signaling in tissue derived from IAV-infected animals. RNA-seq of 31dpi thoracic DRGs from SARS-CoV-2-infected animals highlighted a uniquely neuropathic transcriptomic landscape, which was consistent with substantial SARS-CoV-2-specific mechanical hypersensitivity at 28dpi. Ontology analysis of 1, 4, and 30dpi RNA-seq revealed novel targets for pain management, such as ILF3. Meta-analysis of all SARS-CoV-2 RNA-seq timepoints against preclinical pain model datasets highlighted both conserved and unique pro-nociceptive gene expression changes following infection. Overall, this work elucidates novel transcriptomic signatures triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities while also highlighting several therapeutic targets for alleviation of infection-induced hypersensitivity.

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“…CB2 receptor was co-expressed with. G oA dissociation BRET2 assays were performed as previously described with minor modifications 63 . In brief, HEK293T cells were co-transfected overnight with human CB2 receptor, G αo A-Rluc, G β3 , and G γ9 -GFP2 constructs.…”

Section: Functional Assaysmentioning

confidence: 99%

Large library docking for cannabinoid-1 receptor agonists with reduced side effects

Tummino

Iliopoulos‐Tsoutsouvas

Bráz

et al. 2023

Preprint

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Docking tangible virtual libraries can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones forde novosynthesis and testing. Nine were active by radioligand competition, with > 50% radioligand displacement, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki= 731 nM) led to‘3234, a 1.9 nM binder and a full CB1 agonist. A cryo-EM structure of the‘3234-CB1-Gi1complex confirmed its docked pose, providing a template for further optimization. The new agonist was strongly analgesic especially against thermal pain, with a 10-fold therapeutic window over sedation and no observable catalepsy or conditioned place preference or aversion. These findings suggest that new cannabinoid chemotypes may be able to disentangle the characteristic “tetrad” side-effects from its desired analgesic effect, supporting the further development of cannabinoids as pain therapeutics.

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A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects

Cited by 25 publications

References 34 publications

Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

Large library docking for cannabinoid-1 receptor agonists with reduced side effects

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A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects

Cited by 25 publications

References 34 publications

Design, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

Design, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

Large library docking for cannabinoid-1 receptor agonists with reduced side effects

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Product

Resources

About

Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2