PF-3845 / Pfizer - LARVOL DELTA

Cafeteria Diet Abstinence Induces Depressive Behavior and Disrupts Endocannabinoid Signaling in Dopaminergic Areas: A Preclinical Study. (PubMed, Curr Neuropharmacol) - "Overall, our results suggest that abstinence from a cafeteria diet provokes emotional disturbances linked to neuroadaptive changes in monoamines and endocannabinoid signalling in brain areas partaking to DA transmission that could partially be restored by the enhancement of endocannabinoid signalling through FAAH inhibition."

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

Fatty acid amide hydrolase inhibition modulates sensory and affective aspects of persistent inflammatory pain in mice depending on mu and delta opioid receptors activity: involvement of heme oxygenase 1 enzyme (Neuroscience 2024) - "Male BALB/c mice were submitted to seven days of persistent inflammatory pain (CFA injection into the right hind paw; saline as control) and then systemic treated with a FAAH inhibitor (PF3845), a HO-1 inducer (CoPP) or vehicle (VEHI), combined with a DOR antagonist (naltridole, NTI), a MOR antagonist (CTAP), an HO-1 inhibitor (SnPP) or VEHI (n = 8 per group)...NTI effect on PEAP may be more related to an anxiety behavior than to a decreased pain aversion. Moreover, the amygdala may play an essential role in the endocannabinoid mechanisms of pain processing and modulation and can be a spot for an interaction among endocannabinoid system, HO-1 and opioid receptors."

Preclinical • CNS Disorders • Mood Disorders • Pain • Psychiatry • HMOX1

Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration. (PubMed, Pharmaceuticals (Basel)) - "Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target...Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Infectious Disease • Inflammation • Sleep Disorder

Inhibition of endocannabinoid catabolizing enzyme fatty acid amide hydrolase to reduce chronic neuropathic pain following spinal cord injury (Neuroscience 2023) - "In voltage clamp experiments in SCI-nociceptors, the interspike T-type calcium charge dropped from 56±18 pC/pF (n=12) in control to 10±3 pC/pF (n=12) in the presence of 5 µM PF3845. Taken together, our data suggest that inhibition of FAAH reduces the activity of T-type calcium channels in SCI-nociceptors and reduces both mechanical hypersensitivity and spontaneous pain following SCI."

CNS Disorders • Depression • Neuralgia • Pain • Psychiatry

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

Inhibitors of Endocannabinoids' Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice. (PubMed, Int J Mol Sci) - "Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids' concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Psychiatry • Schizophrenia

Anxiolytic effects of endocannabinoid enhancing compounds: A systematic review and meta-analysis. (PubMed, Eur Neuropsychopharmacol) - "We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications."

Journal • Retrospective data • Review • CNS Disorders • Mood Disorders • Psychiatry

Role of FAAH C385A and BDNF Val66Met Genetic Polymorphisms in Fear Generalization and Anxiety Like-Behaviors (SOBP 2023) - "Methods A fear generalization paradigm with tone-paired 0.3 mV or 1 mV foot shocks was used to study fear discrimination and extinction in FAAH C385A mice and in WT mice injected with FAAH inhibitor, PF-3845...We then showed that BDNFMet/MetFAAHA/A double knock-in mice showed a diminished anxiety-related phenotype compared to BDNFMet/Met mice (n=17 per group, p<0.01). Conclusions Overall, we demonstrate the interplay of the endocannabinoid and neurotrophic system in fear generalization and anxiety-like behaviors in mice, with potential implications for refined treatment of mood and anxiety-based disorders."

Mood Disorders • Psychiatry • BDNF

Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF-3845: A regional analysis of the contribution of endocannabinoid signaling machinery. (PubMed, Int J Eat Disord) - "Overall, our results suggest that emotional disturbances associated with dieting are coupled with region-specific alterations in the cerebral expression of the ECS and that the enhancement of the endocannabinoid signaling by FAAH inhibition might represent a novel pharmacological strategy for the treatment of anxiety related to abstinence from palatable food."

Journal • Genetic Disorders • Mood Disorders • Obesity • 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

Fatty acid amide hydrolase activity in the dorsal PAG attenuates neuropathic pain and associated dysautonomia. (PubMed, Am J Physiol Regul Integr Comp Physiol) - "Administration of the FAAH inhibitor PF-3845 into the dPAG reduces hyperalgesia behavior and the decrease in sympathetic tone induced by SNI...No sex differences were identified. These data support an integrative role for AEA/CB1 receptor signaling in the dPAG contributing to the regulation of both hyperalgesia behavior and altered sympathetic tone in neuropathic pain."

Journal • Neuralgia • Pain

The role of anandamide in hypoglutamatergic psychosis-like disease states (CAN-ACN 2022) - "At baseline, EC lipids were altered in the GluN1KD's compared to their wild-types and following acute PF-3845 (10 mg/kg i.p), fluctuations in EC signalling were greater in the wild-type mice. These results suggest that changes in GluN1KD baseline EC tone may make certain behaviours responsive to elevations of AEA however, further investigation is required."

CNS Disorders • Psychiatry

Inhibitory Neurotransmission Is Sex-Dependently Affected by Tat Expression in Transgenic Mice and Suppressed by the Fatty Acid Amide Hydrolase Enzyme Inhibitor PF3845 via Cannabinoid Type-1 Receptor Mechanisms. (PubMed, Cells) - "(4) Conclusion. Results highlight sex- and/or Tat-dependent alterations of GABAergic activity and eCB signaling in the prefrontal cortex of Tat transgenic mice and further increase our understanding about the role of FAAH inhibition in neuroHIV."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Infectious Disease

Targeting the endocannabinoid system for management of HIV-associated neuropathic pain: A systematic review. (PubMed, IBRO Neurosci Rep) - "Ten preclinical studies found that the endocannabinoids (2-AG and AEA), synthetic mixed CB1R/CB2R agonist WIN 55,212-2, a CB2R-selective phytocannabinoid β-caryophyllene, synthetic CB2R-selective agonists (AM1710, JWH015, JWH133 and Gp1a, but not HU308); FAAH inhibitors (palmitoylallylamide, URB597 and PF-3845) and a drug combination of indomethacin plus minocycline, which produces its effects in a CBR-dependent manner, either prevented the development of and/or attenuated established HIV-NP. Clinical evidence shows that smoked cannabis alleviates HIV-NP. Further research is needed to find out if non-psychoactive drugs that target the ECS and are delivered by other routes than smoking could be useful as treatment options for HIV-NP."

Journal • Review • Human Immunodeficiency Virus • Immunology • Infectious Disease • Neuralgia • Pain • Peripheral Neuropathic Pain

[VIRTUAL] Effects of Endocannabinoid Catabolic Enzyme Inhibitors on Pain-Depressed Nesting (IASP 2021) - "Dose-effect curves were assessed for the following inhibitors in order of MAGL-to FAAH-selectivity: MJN110, JZL184, JZL195, SA57, URB-597, and PF3845. These results provide modest support for further consideration of MAGL-selective inhibitors such as MJN110 as candidate analgesics, with future work needed to assess sex-dependent effects and tolerance. MJN110 was more effective in this study than THC, but it should be noted that none of the eCB-CEIs were as effective as ketoprofen."

CNS Disorders • Depression • Pain • Psychiatry

Rediscovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis. (PubMed, J Biol Chem) - "PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound."

Journal • Infectious Disease • Respiratory Diseases • Tuberculosis

GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration. (PubMed, Exp Neurol) - "We found that a purported GPR18 antagonist, CID-85469571, blocked the neuroprotective effects of PF3845 in all experiments. Collectively, these experiments increase understanding of the role of FAAH inhibition and Tat in mediating microglial neurotoxicity in the HAND condition."

Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • CCL2 • MMP9

PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo. (PubMed, Int J Mol Sci) - "Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases."

Journal • Preclinical • Dental Disorders • Fibrosarcoma • Oncology • Osteoporosis • Periodontitis • Sarcoma • Solid Tumor

Behavioral Battery for Testing Candidate Analgesics in Mice. II.Effects of Endocannabinoid Catabolic Enzyme Inhibitors and ∆9-Tetrahydrocannabinol. (PubMed, J Pharmacol Exp Ther) - "MJN110 effects on IP acid-depressed nesting had a slow onset and long duration (40min to 6hr), were blocked by rimonabant, and tended to be greater in females...PF3845, the most FAAH-selective inhibitor, produced no antinociception up to doses that disrupted locomotion...Significance Statement This study characterized a spectrum of endocannabinoid (eCB) catabolic enzyme inhibitors ranging in selectivity from monoacylglycerol lipase- (MAGL-) selective to fatty acid amide hydrolase- (FAAH-) selective in a battery of pain-stimulated, pain-depressed, and pain-independent behaviors previously pharmacologically characterized in a companion paper. This battery provides a method for prioritizing candidate analgesics by effectiveness to alleviate pain-related behaviors at doses that do not alter pain-independent behaviors, with inclusion of pain-depressed behaviors increasing translational validity and decreasing susceptibility to motor-depressant false positives."

Journal • CNS Disorders • Depression • Pain • Psychiatry

Mini-review: The therapeutic role of cannabinoids in neuroHIV. (PubMed, Neurosci Lett) - "This will be followed by summarizing the current clinical and preclinical findings on the effects of cannabis use and cannabinoids in the context of HIV-1 infection, with specifically focusing on viral load, cognition, inflammation, and neuroprotection. Lastly, we present some potential future directions to better understand the involvement of the eCB system and the role that cannabis use and cannabinoids play in neuroHIV."

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

Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex. (PubMed, Neurobiol Stress) - "Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle...Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress."

Journal • Mood Disorders • Psychiatry

Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis. (PubMed, J Biol Chem) - " PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound."

Journal • Infectious Disease • Respiratory Diseases • Tuberculosis

Mechanism of diuresis and natriuresis by cannabinoids: evidence for inhibition of Na+,K+-ATPase in mouse kidney thick ascending limb tubules. (PubMed, J Pharmacol Exp Ther) - "Here we show that these effects are blocked by the CBR Type I (CB1) inverse agonist, rimonabant...The effect of direct (CP55940 (CP) or AEA) or indirect (fatty acyl amide hydrolase (FAAH) inhibitor, PF3845 (PF)) cannabinoidimetics on Na transport in isolated mouse TAL tubules was studied using the Na-sensitive dye, SBFI-AM...Significance Statement Cannabinoids including endocannabinoids induce renal urine and salt excretion and are proposed to play a physiological role in the regulation of blood pressure. Our data suggest that the mechanism of the cannabinoids involves inhibition of the sodium pump, Na+,K+-ATPase, in thick ascending limb cells and, likely, other proximal and distal tubular segments of the kidney nephron."

Journal • Preclinical

Inhibitory Control Deficits Associated with Upregulation of CBR in the HIV-1 Tat Transgenic Mouse Model of Hand. (PubMed, J Neuroimmune Pharmacol) - "The increase in sEPSC frequency was significantly attenuated by bath application of PF3845, a fatty acid amide hydrolase (FAAH) enzyme inhibitor (p < .001)...Graphical Abstract Results of the Go/No-Go operant conditioning task reveal inhibitory control deficits in female transgenic Tat(+) mice without significantly affecting males. The demonstrated inhibitory control deficits appear to be associated with an upregulation of cannabinoid type 1 receptors (CBR) in the infralimbic (IL) cortex in the same female Tat(+) group."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Infectious Disease

Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression. (PubMed, Brain Behav Immun) - "Intra plantar administration of PF3845 (1 μg/10 μl) or MJN110 (1 μg/10 μl), inhibitors of AEA and 2-AG catabolism respectively, attenuated formalin-evoked hyperalgesia in IFN-α, but not saline-, treated mice. In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression."

Journal • Preclinical • CNS Disorders • Depression • Hepatology • Immunology • Inflammation • Mood Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Oncology • Orthopedics • Pain