A-967079 / AbbVie - LARVOL DELTA

Discovery of A-967079 as an Enterovirus D68 Antiviral by Targeting the Viral 2C Protein. (PubMed, ACS Infect Dis) - "Pharmacological characterization of the mechanism of action involving time-of-addition, resistance selection, and differential scanning fluorimetry assays suggests that viral 2C protein is the drug target. Overall, A-967079 represents a promising candidate for further development as an EV-D68 antiviral."

Journal • CNS Disorders • Infectious Disease • Respiratory Diseases

Transient Receptor Potential Ankyrin 1 is Involved in Zebrafish Painful Neuropathy (IASP 2024) - "elicited a dose-dependent increase in locomotor activity in zebrafish larvae as well as an acute nociceptive response (tail coils) and subsequent sensitization to light touch, that were abolished by the pretreatment with a selective TRPA1 antagonist A967079. Our data indicate that TRPA1 appears to exert a dual activity in oxaliplatin-evoked pain-like responses in zebrafish larvae: first, it is gated by the oxidative stress burden generated by oxaliplatin and by amplifying oxidative stress sustains the pain-like signal. Therefore TRPA1, via its activation by oxidative stress by-products, is necessary and sufficient to produce a neuropathy paradigm in a zebrafish model of CIPN. Zebrafish may represent a suitable model to study TRPA1 in the nociceptive behaviour evoked by oxaliplatin-induced CIPN and associated with ROS production."

Pain • Peripheral Neuropathic Pain

TRPA1 Participates in Reserpine-induced Painful and Comorbid Symptoms in an Experimental Fibromyalgi (IASP 2024) - "Pharmacological therapy for symptom relief consists of pregabalin, duloxetine, or milnacipran use2...A967079, a TRPA1 antagonist, reversed the reserpine-induced pain, fatigue, anxiety, and depressive-like symptoms... The current study confirms the involvement of channel TRPA1 on the pain and comorbid symptoms induced by reserpine in a reserpine-induced fibromyalgia model in mice. The TRPA1 antagonist showed improved effects on fibromyalgia symptoms than drugs currently used to treat fibromyalgia. The use of knockout animals reinforces the TRPA1 role in this condition."

CNS Disorders • Depression • Fatigue • Fibromyalgia • Migraine • Mood Disorders • Musculoskeletal Pain • Pain • Psychiatry • Rheumatology • TRPA1

Calcitonin gene related peptide mediates transient receptor potential ankyrin 1 in Schwann cells (IASP 2024) - "The CGRP effect was measured also in the presence of antagonists of CGRP (CGRP8-37 and olcegepant) and TRPA1 (A967079) receptors, and inhibitors of adenylyl cyclase (SQ22536), NOS (L-NAME), PKA (H89), NOX1 (ML171) and a ROS scavenger (PBN)... These results showed that CGRP, by targeting its receptor in SCs, liberates NO, which activates SC TRPA1. Activated TRPA1 promotes a Ca2+-dependent H2O2 production that sustains a feed-forward mechanism comprising TRPA1 channel engagement and ROS release."

CNS Disorders • Migraine • Pain • TRPA1

Design of Novel TRPA1 Agonists Based on Structure of Natural Vasodilator Carvacrol-In Vitro and In Silico Studies. (PubMed, Pharmaceutics) - "In an isolated tissue bath experiment, it was shown that 1 µM of the selective TRPA1 antagonist A967079 significantly (p < 0.001) reduced vasodilation induced by 3 mM of carvacrol...In conclusion, carvacrol-induced vasodilation is partly mediated by the activation of TRPA1 channels. Combining different in silico approaches pointed out that the molecule D27 (2-[2-(hydroxymethyl)-4-methylphenyl]acetamide) is the best candidate for further synthesis and experimental evaluation in in vitro conditions."

Journal • Preclinical • Cardiovascular • Hypertension

Schwann Cells IGF-1 receptor intracellular signaling promotes an endothelial nitric oxide synthase-mediated Transient receptor potential ankyrin 1 (TRPA1) activation (EACR 2024) - "The IGF-1 effect was measured also in the presence of antagonists of IGF-1 receptor (IGF1-R) (PPP) and TRPA1 (A967079) receptors and inhibitors of: the IRS-1 (NT157), the Akt (Akti-1/2), eNOS (L-NAME) and a NO scavenger (cPTIO). The ensuing IGF-1R activation in SCs promotes an eNOS-mediated TRPA1 activation and release of reactive oxygen species that targets SC TRPA1. Glial cell-selective targeting of the various mediators that sustain cascade signals initiated by SC IGF-1R activation could be a promising area for future treatments against MBCP."

Breast Cancer • Immunology • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor • IGF1 • NOS3 • TRPA1

Transient Receptor Potential Ankyrin 1 Channel Alters Transforming Growth Factor Beta 1/Smad Signaling in Rat Vocal Fold Fibroblasts. (PubMed, Laryngoscope) - "VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF-β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti-fibrotic mechanisms of TRPA1 activation through TGF-β1/Smad signaling in VFFs."

Journal • Preclinical • Fibrosis • Immunology • ACTA2 • COL1A1 • HAS1 • SMAD3 • SMAD7 • TGFB1 • TRPA1

Requirement of TRPA1 in Oxidized Phosphatidylcholine Induced Pro-inflammatory Gene Expression by Human Airway Fibroblasts (ATS 2024) - "We also used the TRPA1 selective inhibitor, A967079 (1µM) and qRT-PCR to examine the role of TRPA1 in OxPAPC (80µg/mL, 24hrs)-induced mRNA for cyclooxygenase-2 (COX2) and interleukin-8 (IL-8)... Our data reveal that HAF expresses abundant TRPA1 that is activated by OxPAPC and required for OxPAPC-induced expression of pro-inflammatory genes. Thus, OxPAPC may modulate the contribution of HAF to asthma-associated pathobiology. Funding: Canada Research Chairs Program and Children's Hospital Research Institute of Manitoba"

Asthma • Pulmonary Disease • Respiratory Diseases • CXCL8 • TRPA1

EFFECT OF APREPITANT ON ALLYL ISHOTHIOCYANATE-INDUCED MUCOSAL INFLAMMATION AND GASTRIC MOTILITY IMPAIRMENT IN THE RODENT STOMACH (DDW 2024) - "Previously we have shown that the oral administration of allyl isothiocyanate (AITC) produced gastric motility impairment without the hemorrhagic gastric lesions in rodents and that the model was easily accessible to evaluation of the prokinetic agents such as an itopride and a mosapride (JPS 0 1)...And A-967079 (10 mM) a TRPA1 channel blocker was given into gastric mucosa 30 min before AITC application...The mucosal vascular permeability induced by AITC was significantly attenuated by the pretreatment of an indomethacin or an aprepitant but not a BIBN 4096... These results suggest that AITC-induced mucosal inflammation with no mucosal damage is dependent on substance P and endogenous prostaglandin in rodent stomachs. Those inflammation may lead to the impaired motility in rodents."

Preclinical • Anesthesia • Dyspepsia • Hematological Disorders • Inflammation • Mucositis • TRPA1

Ammonium chloride-induced hypothermia is attenuated by transient receptor potential channel vanilloid-1, but augmented by ankyrin-1 in rodents. (PubMed, Life Sci) - "TRPV1 channels limit, whereas TRPA1 channels exaggerate the development of NH4Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular Tb control and careful consideration of NH4Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions."

Journal • Preclinical

Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8 (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Medical University of Vienna | Not yet recruiting ➔ Completed

Trial completion • Pain

TRPA1-PI3K/Akt-OPA1-ferroptosis axis in ozone-induced bronchial epithelial cell and lung injury. (PubMed, Sci Total Environ) - "Exposure to ozone induces mitochondrial dysfunction in human bronchial epithelial cells and mouse lungs by activating TRPA1, which results in ferroptosis mediated via a PI3K/Akt/OPA1 axis. This supports a potential role of TRPA1 blockade in preventing the deleterious effects of ozone."

Journal • Immunology • Inflammation • Metabolic Disorders • Ocular Inflammation • Respiratory Diseases • OPA1 • TRPA1

Pharmacologic inhibition of TRPA1 counteract tear gas induced cutaneous injuries. (PubMed, J Pharmacol Exp Ther) - "The TRPA1 inhibitor HC-030031 or A-967079 was administered post-CS exposure...Exposure to CS tear gas agents has been believed to cause transient acute toxic effects that are minimal at most. Here, we found that CS tear gas exposure causes both acute and persistent skin injuries, and that treatment with transient receptor potential ion channel ankyrin 1 (TRPA1) antagonists ameliorated skin injuries."

Journal • CNS Disorders • Inflammation • Pain • TRPA1

Mono-2-ethylhexylphthalate (MEHP) is a potent agonist of human TRPA1 channel. (PubMed, Chemosphere) - "MEHP-induced hTRPA1 activation was blocked by the TRPA1 inhibitor A-967079...In addition, the N855S mutation in hTRPA1 associated with familial episodic pain syndrome decreased MEHP-induced hTRPA1 activation. In summary, we report that MEHP is a potent agonist of hTRPA1 which generates new possible mechanisms for toxic effects of phthalates in humans."

Journal • Musculoskeletal Pain • Pain • TRPA1

The involvement of TRPA1 in cocaine addiction in prefrontal-accumbens glutamatergic pathway (Neuroscience 2023) - "To investigate the role of TRPA1 in NAc on cocaine-induced addictive behaviors, several behavioral tests (conditioned place preference (CPP) and CPP reinstatement (RI), hyperlocomotion, and behavioral sensitization) were performed in C57BL/6J mice, while regulating TRPA1 in NAc with TRPA1 antagonist, A967079, treatment...TRPA1 can regulate cocaine addiction presumably by hindering glutamatergic transmission extending from mPFC to NAc and CAMKII signaling might be the underlying mechanism. (Supported By a grant 2022R1A6A1A03054419 from the NRF)"

CNS Disorders • Psychiatry • Tobacco Addiction • TRPA1

Characterization of Bovine Adrenal Medulla as a New Surrogate Model of Non-histaminergic Itch (clinicaltrials.gov) - P=N/A | N=22 | Completed | Sponsor: Aalborg University | Recruiting ➔ Completed

Trial completion

Functional dynamics and allosteric modulation of TRPA1. (PubMed, Structure) - "In subsequent experiments, we found that mutations that disrupt packing of the S4-S5 linker-TRP-like domain and the S5 and S6 helices also affected channel activity. In simulations, we also observed A-967079, a known allosteric inhibitor, binding between helices S5 and S6, suggesting that A-967079 may suppress activity by stabilizing a non-conducting pore conformation-a finding consistent with our proposed gating mechanism."

Journal • TRPA1

Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8 (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Medical University of Vienna

New P1 trial • Pain

Kinin B and B Receptors Activation Sensitize the TRPA1 Channel Contributing to Anastrozole-Induced Pain Symptoms. (PubMed, Pharmaceutics) - "All painful symptoms were reduced by BR (Icatibant), BR (DALBk), or TRPA1 (A967079) antagonists. TRPA1 seems to be sensitized by mechanisms dependent on the activation of PLC/PKC, and PKA due to kinin receptors stimulation in anastrozole-treated animals. Thus, regulating this signaling pathway could contribute to alleviating AIs-related pain symptoms, patients' adherence to therapy, and disease control."

Journal • Musculoskeletal Diseases • Musculoskeletal Pain • Pain • TRPA1

CYP1B1-derived epoxides modulate the TRPA1 channel in chronic pain. (PubMed, Acta Pharm Sin B) - "TRPA1 activation by 8,9-EET and 19,20-EpDPA was attenuated by the antagonist A967079, and mouse TRPA1 was more responsive to 8,9-EET and 19,20-EpDPA than human TRPA1...Similarly, Cyp1b1-knockout mice displayed a reduced chronic pain phenotype following SNL injury. These data suggest that manipulation of the CYP1B1-oxylipin-TRPA1 axis might have therapeutic benefit."

Journal • Immunology • Inflammation • Pain • CYP1B1 • TRPA1

Transient receptor potential Ankyrin-1 (TRPA1) agonists suppress myelination and induce demyelination in organotypic cortical slices. (PubMed, Glia) - "This does not occur when the TRPA1 antagonist, A967079, is also applied. Of note is that when TRPA1 agonists are applied for either 24 h, 3 days or 7 days, axon integrity appears to be preserved while mature myelinated oligodendrocytes remain but with significantly shortened internodes. These results provide further evidence that TRPA1 inhibition could be protective in demyelination diseases and a promising therapy to prevent demyelination and promote remyelination."

Journal • Cardiovascular • CNS Disorders • Multiple Sclerosis • Solid Tumor

Bipartite Activation of Sensory Neurons by a TRPA1 Agonist Allyl Isothiocyanate Is Reflected by Complex Ca Influx and CGRP Release Patterns: Enhancement by NGF and Inhibition with VAMP and SNAP-25 Cleaving Botulinum Neurotoxins. (PubMed, Int J Mol Sci) - "These signals were all blocked by two TRPA1 antagonists, HC-030031 and A967079...Both toxins blocked NGF-induced neuropeptide secretion and its enhancement of the response to AITC. In conclusion, NGF sensitisation of sensory neurons involves TRPA1, elevated Ca influx, and CGRP exocytosis, mediated by VAMP1/2/3 and SNAP-25 which can be attenuated by the BoNTs."

Journal • CNS Disorders • Migraine • Pain • TRPV1

Anti-Inflammatory Effects of Cannabigerol in Rheumatoid Arthritis Synovial Fibroblasts and Peripheral Blood Mononuclear Cell Cultures Are Partly Mediated by TRPA1. (PubMed, Int J Mol Sci) - "However, effects on PBMCs were only partially mediated by TRPA1 as the antagonist A967079 did inhibit some but not all effects of CBG on cytokine production...CBG showed broad anti-inflammatory effects in isolated RASF, PBMC and PBMC/RASF co-cultures. As CBG is non-psychotropic, it might be used as add-on therapy in RA to reduce IL-6 and autoantibody levels."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Oncology • Pain • Rheumatoid Arthritis • Rheumatology • CXCL8 • IL10 • IL6 • TNFA • TRPA1

The antimalarial artemisinin is a non-electrophilic agonist of the transient receptor potential ankyrin type 1 receptor-channel. (PubMed, Eur J Pharmacol) - "Artemisinin was able to evoke calcium transients in HEK293T cells expressing recombinant human TRPA1, as well as in a subpopulation of mouse dorsal root ganglion (DRG) neurons which also responded to the selective TRPA1 agonist allyl isothiocyanate (AITC) and these responses were reversibly abolished by the selective TRPA1 antagonist A967079...Interestingly, using human TRPA1 mutants, we demonstrate that artemisinin acts as a non-electrophilic agonist of TRPA1, activating the channel in a similar manner to carvacrol and menthol. These results may provide a better understanding of the biological actions of the very important antimalarial and anti-tumour agent artemisinin."

Journal • Infectious Disease • Malaria • Oncology • Pain

TRPA1 participation in behavioral impairment induced by chronic corticosterone administration. (PubMed, Psychopharmacology (Berl)) - "Our work suggests that TRPA1 channel appears crucial to mediate the behavioral impairment induced by CCA in male Swiss mice."

Journal • CNS Disorders • Depression • Immunology • Inflammation • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • TRPA1