MJN110 / Scripps Research Institute - LARVOL DELTA

Enhancement of 2-arachidonoylglycerol but not anandamide signaling in the ventral tegmental area selectively increases the choice to respond to reward-predictive incentive cues in male rats. (PubMed, Neuropharmacology) - "We microinfused MJN110 or PF3845, a fatty acid amide hydrolase (FAAH) inhibitor, into the VTA to increase 2-AG and anandamide, respectively in male rats...Further, the intra-VTA MJN110 enhancement of responding to ICs was blocked by the CB1 receptor antagonist rimonabant. Our results suggest that increasing 2-AG, but not anandamide, in the VTA selectively enhances the choice to respond to cues predicting a reward. However, the effects of systemic MJN110 in enhancing the vigor of responding cannot be attributed to VTA 2-AG signaling."

Journal • Preclinical

Dissociable peripheral and central mechanisms of monoacylglycerol lipase inhibition on pain- and depression-related behaviors in a rat model of neuropathic pain. (PubMed, Pain) - "We examined the behavioral, electrophysiological, and receptor-specific effects of the MGL inhibitor MJN110 in rats with spared nerve injury...High-dose MGL inhibition reduces sensory hypersensitivity via activation of peripheral CB1Rs on DRG neurons. These findings identify dose- and site-specific CB1R mechanisms for separating the sensory and affective dimensions of pain and support endocannabinoid augmentation as a dual antidepressant-antinociceptive strategy in chronic pain comorbidity."

Journal • Preclinical • CNS Disorders • Depression • Immunology • Neuralgia • Pain • Psychiatry

Inhibiting hepatocytes MAGL alleviates osteoporosis caused by high-fat diet-induced liver fibrosis in male mice. (PubMed, J Endocr Soc) - "Notably, osteoclast activation in the femoral germinal layer of mice with liver fibrosis was elevated, whereas this activation was attenuated in the MJN110-treated group. In conclusion, these findings suggest that hepatic MAGL inhibition can alleviate femoral osteoclast activation and bone destruction associated with high-fat diet-induced liver fibrosis, offering a novel therapeutic avenue for hepatic osteoporosis."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Osteoporosis • Rheumatology • MGLL • SMAD3

Covalent Inhibitors of Monoacylglycerol Lipase Induce Conformational Changes and Proteasomal Degradation. (PubMed, J Am Chem Soc) - "Carbamate/urea inhibitors such as MJN110, JZL184, and SAR629 are widely used to irreversibly inhibit MGLL through covalent modification of the catalytic serine residue...We show that loss of MGLL following covalent inhibitor treatment is dependent on the 26S proteasome, while detailed simulations of MGLL dynamics following inhibitor binding suggest that these inhibitors do not destabilize their protein target but instead induce conformational changes that likely facilitate polyubiquitination by exposing two lysine residues. Taken together, these findings establish carbamate/urea inhibitors as dual functional molecules with the propensity to both covalently inhibit their target and act as structural degraders, potentially functioning as monovalent molecular glues, highlighting the need to evaluate the degradation potential alongside inhibitory potency in future screening and drug discovery."

Journal • Infectious Disease • Oncology • Targeted Protein Degradation

Acute Pain After Total Knee Arthroplasty: 2-Arachidonoylglycerol Tone and Endocannabinoid/Eicosanoid Crosstalk. (PubMed, Anesth Analg) - "Our findings demonstrate that patients presenting with an elevated 2-AG tone develop greater postoperative pain and position MAGL as an enzymatic node linking 2-AG metabolism with eicosanoid biosynthesis in perioperative human tissue."

Journal • Orthopedics • Pain

The Monoacylglycerol Lipase Inhibitor MJN110 Produces Analgesia in Chronic Inflammatory Pain and Enhances the Incentive Salience of Reward Predictive Cues (CPDD 2025) - "Our results suggest that MJN110 is an effective analgesic, possibly by altering pain affect, but its clinical utility may be complicated by the enhancement of reward seeking."

Pain

Endocannabinoid Tone is Associated with Acute Pain After Total Knee Arthroplasty (IARS-SOCCA 2025) - "Mice were treated with the MAGL inhibitor MJN110 (5 mg/kg, i.p.) and levels of 2-AG, AA, and eicosanoids were quantified via mass spectrometry... 2-AG is positively correlated with postoperative pain, with stronger associations observed in females. These findings indicate that patients presenting with elevated 2-AG levels develop greater postoperative pain in line with the 2-AG/eicosanoid crosstalk model."

Anesthesia • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Musculoskeletal Diseases • Orthopedics • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology

Endocannabinoid Tone is Associated with Acute Pain After Total Knee Arthroplasty (IARS-SOCCA 2025) - "Mice were treated with the MAGL inhibitor MJN110 (5 mg/kg, i.p.) and levels of 2-AG, AA, and eicosanoids were quantified via mass spectrometry... 2-AG is positively correlated with postoperative pain, with stronger associations observed in females. These findings indicate that patients presenting with elevated 2-AG levels develop greater postoperative pain in line with the 2-AG/eicosanoid crosstalk model."

Anesthesia • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Musculoskeletal Diseases • Orthopedics • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology

Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain. (PubMed, Cannabis Cannabinoid Res) - "The dose-dependent anti-allodynic effects of the MAGL inhibitors (irreversible MAGL inhibitor [JZL184] and selective MAGL inhibitor [MJN110]) and the NSAID diclofenac, as well as the additive potential of combined MAGL and cyclooxygenase (COX) inhibition, were assessed...Similarly, the anti-allodynic effects of the CB2-selective agonist (LY2828360) were tested...The anti-allodynic effects of JZL184 (40 mg/kg) were blocked by pre-treatment of the CB2 antagonist SR144528 (3 mg/kg) but not the CB1-selective antagonist rimonabant (SR141716A; 3 mg/kg), suggesting a CB2-mediated mechanism of anti-allodynia via MAGL inhibition...Finally, HPI per se increased pro-inflammatory cytokine levels, which were unaltered by MAGL inhibition despite the anti-allodynia assessed behaviorally. These data support simultaneously targeting endocannabinoids and COX enzymes as a potential post-operative pain management approach."

Journal • Pain

Inhibition of 2-AG hydrolysis alleviates posttraumatic headache attributed to mild traumatic brain injury. (PubMed, J Headache Pain) - "Enhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation."

Journal • CNS Disorders • Immunology • Migraine • Pain • Vascular Neurology

A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation. (PubMed, Front Immunol) - "Lastly, selected HETE-related inflammatory lipid mediators in the striatum were downregulated by chronic MJN110 treatment. These findings demonstrate anti-inflammatory and neuroprotective properties of MJN110 without cannabimimetic behavioral effects and suggest a promising alternative to cannabis for managing neuroinflammation."

Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Infectious Disease • Inflammation • GFAP

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor after spinal cord injury (AUA 2024) - "We investigated the effect of MAGL inhibitor, MJN110, in the mouse with neurogenic lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI)... MAGL inhibition can improve LUTD by attenuation of DO after SCI. MAGL can be a therapeutic target for neurogenic LUTD after SCI."

CNS Disorders • Orthopedics • TRPA1

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury. (PubMed, Neurourol Urodyn) - "MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI."

Journal • Preclinical • CNS Disorders • Orthopedics • TRPA1 • TRPV1

Function of Presynaptic Inhibitory Cannabinoid CB Receptors in Spontaneously Hypertensive Rats and Its Modification by Enhanced Endocannabinoid Tone. (PubMed, Int J Mol Sci) - "The effect of CP55940 was abolished/reduced by the CB receptor antagonist AM251 (in both groups) and in WKY by endocannabinoid degradation blockade, i.e., the monoacylglycerol lipase (MAGL) inhibitor MJN110 and the dual fatty acid amide hydrolase (FAAH)/MAGL inhibitor JZL195 but not the FAAH inhibitor URB597. In conclusion, the function of presynaptic inhibitory CB receptors depends on the hypertension model. Although no differences occurred between SHR and WKY under basal experimental conditions, the CB receptor function was better preserved in SHR when the endocannabinoid tone was increased by the inhibition of MAGL or the endocannabinoid transporter."

Journal • Preclinical • Cardiovascular • Hypertension

Effects of Repeated Treatment with the Monoacylglycerol Lipase Inhibitor MJN110 on Pain-Related Depression of Nesting and Cannabinoid 1 Receptor Function in Male and Female Mice. (PubMed, J Pharmacol Exp Ther) - "This study used an assay of pain-related behavioral depression in mice to show that repeated MJN110 treatment produced (1) weak but sustained antinociception in male mice, (2) antinociceptive tolerance in females, and (3) modest cannabinoid-receptor desensitization that varied by region and sex. Antinociceptive tolerance may limit the utility of MJN110 for treatment of pain."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

The Bidirectional Effect of 2-AG on Hyperdopaminergic States: Implications for Therapeutic 2-AG Modulation in Psychosis (ACNP 2023) - " Genetic (adult dopamine transporter-knockout (DATKO)) and pharmacological (C57Bl/6J with amphetamine) models of hyperDA were treated acutely with a MAGLi (MJN110, 5mg/kg) or DAGLi (DO34, 30mg/kg), and tested on several behavioural assays. The present study applied behavioural pharmacology combined with molecular, lipidomic, and PET imaging studies to demonstrate profound brain-region specific remodelling of 2-AG in hyperDA states. The work highlights hitherto unrecognized potential for detrimental effects of MAGLi in certain disease states or hyperDA pathologies. It also revealed a potential therapeutic approach to ameliorate hyperDA pathologies with indirect modulation of DA by reducing 2-AG synthesis via DAGLi."

ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Bipolar Disorder • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • Schizophrenia • Tourette Syndrome

A Novel Prefrontal Cortex Glucocorticoid and Endocannabinoid Mechanism Critical to the Potentiation Effect of Mild Stress on Drug Reexposure-Induced Relapse in Rats (ACNP 2023) - "CORT effects are prevented by inhibition of Gq signaling using a palmitoylated peptide incorporating the C terminus of Gαq/11 or by the DAG lipase inhibitor, DO-34, and are reproduced by the MAG lipase inhibitor, MJN110 (p<0.05), suggesting involvement of Gq-dependent PL mobilization of the endocannabinoid, 2-AG. Finally, inhibition of core-projecting PL PNs using an intersectional hM4Di DREADD approach prevented CORT-potentiated cocaine seeking."

Preclinical • CNS Disorders

Inhibition of endocannabinoid catabolic enzymes affects locomotory episode structure in mice (Neuroscience 2023) - "We used selective inhibitors of endocannabinoid degradation enzymes (MJN110 and PF3845) to elevate the signaling of 2-Arachidonoylglycerol (2-AG) and Anandamide (AEA), respectively. Our results indicate that the number of locomotory episodes reflects the overall locomotor activity level, while the microstructure of locomotory behavior remains unchanged. The changes in the locomotory episode structure can provide valuable information about the mechanisms underlying observed behavioral effects."

Preclinical • CNS Disorders

Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells. (PubMed, Cells) - "Antiangiogenic and VEGF-lowering effects were also demonstrated for the MAGL inhibitor MJN110...On the other hand, JZL184 did not exert a direct effect on VEGFR2 activation induced by recombinant VEGF, so there seems to be no downstream effect on already released VEGF. In conclusion, these results reveal a novel mechanism of antiangiogenic action of JZL184 under conditions of hypoxic tumor-endothelial communication."

Journal • Lung Cancer • Oncology • Solid Tumor • KDR

Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration. (PubMed, JHEP Rep) - "Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL) and specifically invalidated in hepatocytes (MAGL) or myeloid cells (MAGL)...By using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Inflammation • Liver Cancer • Metabolic Disorders • Solid Tumor • IFNAR2

Sexually dimorphic effects of monoacylglycerol lipase inhibitor MJN110 on stress-related behaviors and drinking in Marchigian Sardinian alcohol-preferring rats. (PubMed, Br J Pharmacol) - "Acute inhibition of MAGL attenuated some stress-related responses in msP rats but not voluntary alcohol drinking. Our results provide new insights into the sex dimorphism documented in stress-induced responses and suggest that sex-specific endocannabinoid-based approaches should be considered in the clinical development of therapeutics."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Immunology • Mood Disorders • Psychiatry

Inhibition of Monoacylglycerol Lipase Decreases Angiogenic Features of Endothelial Cells via Release of Tissue Inhibitor of Metalloproteinase-1 from Lung Cancer Cells. (PubMed, Cells) - "Comparative experiments with MAGL inhibitors JW651 and MJN110 showed the same results...In addition, JZL184 caused a dose-dependent regression of A549 tumor xenografts in athymic nude mice, which was associated with a decreased number of CD31-positive cells and upregulation of TIMP-1-positive cells in xenograft tissue. In conclusion, our data suggest that elevation of 2-AG by MAGL inhibition leads to increased release of TIMP-1 from lung cancer cells, which mediates an antiangiogenic effect on endothelial cells."

Journal • Lung Cancer • Oncology • Solid Tumor • CD31 • PECAM1 • TIMP1

MAGL regulates synovial macrophage polarization vis inhibition of mitophagy in osteoarthritic pain. (PubMed, Mol Med Rep) - "The OA mice were intraperitoneally injected with MJN110 to inhibit MAGL once a day for a week...MAGL inhibition increased the mechanical and thermal pain thresholds of OA mice and enhanced the mitophagy levels of M1 macrophages. In conclusion, in the present study, it was shown that MAGL regulated synovial macrophage polarization by inhibiting mitophagy in OA."

Journal • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

The Estrous Cycle Influences the Effects of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibition in the Anxiety-Like Behavior in Rats. (PubMed, Cannabis Cannabinoid Res) - " Considering the lack of studies evaluating sex and ECP differences in the eCB system in anxiety, using URB597, a fatty acid amide hydrolase inhibitor, or MJN110, a monoacylglycerol lipase inhibitor, we explored the effects of increasing AEA or 2-AG levels, respectively, in cycling and ovariectomized (OVX) female adult Wistar rats, as well as males, subjected to the elevated plus maze. In OVX females, the anxiolytic-like effect of MJN110 was dependent on low estradiol levels. Together, our findings support the evidence that females react differently to the effects of cannabinoids in the anxiety-like behavior; in addition, AEA and 2-AG modulation elicits anxiety-like responses that are closely influenced by hormone levels, mainly estradiol."

Journal • Preclinical • Mood Disorders • Psychiatry

Targeting T-type calcium channels and the endocannabinoid system to treat SCI-induced neuropathic pain. (Neuroscience 2022) - "In voltage clamp experiments in nociceptors isolated from the same cohort of rats the interspike T-type calcium charge dropped from 75±14 pC/pF (n=18) in control to 39±13 pC/pF (n=14) in the presence of 5 µM MJN110 and to 9±2 pC/pF (n=12) in the presence of 5 µM PF3845. Taken together, our data suggest that inhibition of endocannabinoid catabolizing enzymes MAGL and/or FAAH reduces the activity of T-type calcium channels in SCI-nociceptors and rescues SCI-pain."

CNS Disorders • Neuralgia • Pain