AM4113 / MAKScientific - LARVOL DELTA

Activation of cerebellar endocannabinoid signaling disrupts the reconsolidation of associative fear memory (Neuroscience 2024) - "Male L7::Gq(+)-DREADD mice were exposed to fear conditioning and then a reactivation stimulus, and administered endocannabinoid inhibitor AM4113 (3mg/kg, a CB1R antagonist) immediately after memory reactivation, 30 mins prior to a J60 injection...Thus inhibition of CB1Rs rescued the memory reconsolidation that was disrupted by GqDREADD activation in PCs. Therefore, our results indicate that pharmacological activation of endocannabinoid receptors in the cerebellum impairs the reconsolidation of fear memory in male mice."

CNS Disorders • Cognitive Disorders

Descending mechanism by which medial prefrontal cortex endocannabinoid signaling controls the development of neuropathic pain and neuronal activity of dorsal root ganglion. (PubMed, Pain) - "Elevated dorsal root ganglion neuronal activity after injury was also diminished in rats by mPFC injection of AM4113, potentially by reducing antidromic activity and subsequent neuronal inflammation. These findings suggest that depending on the phase of the pain condition, both blocking and activating CB1 receptors in the mPFC can regulate descending control of pain and affect both dorsal horn neurons and peripheral sensory neurons, contributing to changes in pain sensitivity."

Journal • Inflammation • Neuralgia • Pain

Effects of the CB1 receptor antagonists AM6545 and AM4113 on metabolic syndrome-induced prostatic hyperplasia in rats. (PubMed, Biomol Biomed) - "MetS rats treated with either AM6545 or AM4113 showed reduced concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the prostate compared with the MetS group. In conclusion, the CB1 antagonists AM6545 and AM4113 protect against MetS-induced BPH through their anti-proliferative, antioxidant, and anti-inflammatory effects."

Journal • Preclinical • Benign Prostatic Hyperplasia • Metabolic Disorders • Oncology • CAT • CCND1 • IL6 • TNFA

Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge. (PubMed, Cells) - "Early studies indicated that rimonabant, a selective CB1R antagonist with an inverse agonist profile, was highly promising as a therapeutic for SUDs...Lastly, we discuss the rationale for developing neutral CB1R antagonists as potential treatments for SUDs, the supporting evidence in recent research, and the challenges of this strategy. We conclude that developing neutral CB1R antagonists without inverse agonist profile may represent attractive strategies for the treatment of SUDs."

Journal • Review • CNS Disorders • Depression • Psychiatry

Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review. (PubMed, Front Pharmacol) - "Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene...In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will..."

Journal • Review • Addiction (Opioid and Alcohol)

Effects of the cannabinoid CB-receptor neutral antagonist AM4113 and antagonist/inverse agonist rimonabant on fentanyl discrimination in male rats. (PubMed, Drug Alcohol Depend) - "Results show that the µ-opioid agonists (fentanyl, oxycodone, and morphine) substituted fully and dose-dependently for fentanyl, whereas pretreatment with the µ-opioid antagonist naltrexone antagonized fentanyl's discriminative-stimulus effects. These results extend our recent work showing that AM4113 can effectively block the behavioral effects of heroin without producing rimonabant-like adverse effects. Taken together, these data suggests that CB neutral antagonists effectively block the behavioral effects of structurally distinct morphinan (heroin) and phenylpiperidine-based (fentanyl) opioids and may provide a novel therapeutic option for the treatment of OUD."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Substance Abuse

Investigation on the neuroprotective effect of a cannabidiol-enriched non-psychotropic Cannabis sativa L. extract in an in vitro model of excitotoxicity. (PubMed, Fitoterapia) - "Moreover, CSE completely reversed the reduction of CB1 receptor expression induced by glutamate, and the presence of the CB1 antagonist AM4113 reduced CSE effectiveness, suggesting that CBr play a role in the modulation of neuronal excitotoxicity. This work demonstrated the in vitro effectiveness of CSE as a neuroprotective agent, proposing the whole cannabis phytocomplex as a more effective strategy, compared to its main constituents alone, and suggested further investigations by using more complex cell models before moving to in vivo studies."

Journal • Preclinical • BDNF

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy. (PubMed, Eur J Pain) - "Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain."

Journal • Immunology • Pain • Peripheral Neuropathic Pain • TRPV1

Effects of Cannabinoid Agonists and Antagonists in Rats Discriminating Fentanyl. (PubMed, FASEB J) - "Results show that the µ-opioid agonists (fentanyl, morphine, and oxycodone) substituted fully for fentanyl, whereas the muscarinic antagonist atropine did not substitute for fentanyl. The CB1 agonists Δ9-THC, AM2201, and AM8936 all partially substituted for fentanyl's discriminative-stimulus effects suggesting some overlap in the discriminative-stimulus effects of cannabinoid agonists and fentanyl. Pretreatment studies with a µ-opioid receptor antagonist show that naltrexone antagonized fentanyl's effects...Our findings are consistent with our recent work showing that AM4113 attenuates heroin self-administration in rats, without producing depressive-like effects. Collectively, these data suggests that CB1 neutral antagonists that block CB1 receptors with rimonabant-like potency, devoid of unwanted side-effects, may be therapeutically advantageous for countering the abuse-related behavioral effects of opioids."

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

Role of PI3K/Akt axis in mitigating hippocampal ischemia-reperfusion injury via CB1 receptor stimulation by paracetamol and FAAH inhibitor in rat. (PubMed, Neuropharmacology) - "PAR poses a significant neuroprotective effect which may be mediated, at least in part, via activation of anandamide/CB1/PI3K/Akt pathway in the IR rat model."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Infectious Disease • Novel Coronavirus Disease • Reperfusion Injury • GFAP • MPO

Role of Medial Prefrontal Cortex Endocannabinoids Signaling in Descending Control of Neuropathic Pain (Neuroscience 2021) - "SNI reduced mechanical threshold to induce action potential firing of WDR neurons, which was reversed in rats with mPFC injection of AM4113. These results suggested that eCB-dependent mPFC activity contributes to the pain chronification and manipulation of eCB signaling in mPFC after painful nerve injury can reverse the pain-like behaviors by regulating descending pain control system.; Grant Support: NIH Grant to B.P. R01NS112194"

CNS Disorders • Neuralgia • Pain

CB1 receptor antagonist AM4113 reverts the effects of cannabidiol on cue and stress-induced reinstatement of cocaine-seeking behaviour in mice. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Both, the attenuation of cue-induced reinstatement and the facilitation of stress-induced reestablishment were abolished by AM4113 in cannabidiol 20 mg/kg-treated mice. Our results reveal a series of complex CB1-related changes induced by cannabidiol with a varying impact on the reinstatement of cocaine-seeking behaviour that could limit its therapeutic applications."

Journal • Preclinical • CNS Disorders • Psychiatry • Substance Abuse

CB1 Receptor Neutral Antagonist Treatment Epigenetically Increases Neuropeptide Y Expression and Decreases Alcohol Drinking. (PubMed, Neuropharmacology) - "Additionally, AM4113 treatment increased occupancy of CBP and H3K9/14ac at the Npy gene promoter, leading to an increase in both mRNA and protein levels of NPY in the amygdala. These novel findings suggest that CB1 receptor-mediated CREB signaling plays an important role in the modulation of NPY function through an epigenetic mechanism and further support the potential use of CB1 receptor neutral antagonists for the treatment of alcohol use disorder."

Journal • Addiction (Opioid and Alcohol) • Mood Disorders • Psychiatry • CREB1 • CREBBP

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome. (PubMed, Molecules) - "Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Renal Disease • ALB • TGFB1

Effects of the CB1 Receptor Antagonists AM6545 and AM4113 on Insulin Resistance in a High-Fructose High-Salt Rat Model of Metabolic Syndrome. (PubMed, Medicina (Kaunas)) - "They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral antagonists with improved safety profiles for managing metabolic disorders."

Journal • Preclinical • Cardiovascular • Diabetes • Metabolic Disorders

Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. (PubMed, CNS Drugs) - "Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Genetic Disorders • Obesity