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Activation of cerebellar endocannabinoid signaling disrupts the reconsolidation of associative fear memory (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_7081;
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.
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Preclinical, Journal: Effects of the CB1 receptor antagonists AM6545 and AM4113 on metabolic syndrome-induced prostatic hyperplasia in rats. (Pubmed Central) - May 22, 2023
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.
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Review, Journal: Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge. (Pubmed Central) - Oct 28, 2022
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.
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Preclinical, Journal: Investigation on the neuroprotective effect of a cannabidiol-enriched non-psychotropic Cannabis sativa L. extract in an in vitro model of excitotoxicity. (Pubmed Central) - Oct 1, 2022
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.
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Preclinical, Journal: Effects of Cannabinoid Agonists and Antagonists in Rats Discriminating Fentanyl. (Pubmed Central) - May 14, 2022
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.
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Journal: CB1 Receptor Neutral Antagonist Treatment Epigenetically Increases Neuropeptide Y Expression and Decreases Alcohol Drinking. (Pubmed Central) - Jan 28, 2022
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.
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Role of Medial Prefrontal Cortex Endocannabinoids Signaling in Descending Control of Neuropathic Pain (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_4752;
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
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Journal: Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. (Pubmed Central) - Sep 23, 2020
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.
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Agonist substitution tests with the phytocannabinoid ∆-tetrahydrocannabinol (0.1-1.0 mg/kg), synthetic CB agonists nabilone (0.01-0.1 mg/kg), AM4054 (0.01-0.03 mg/kg), K2/Spice compound JWH-018 (0.03-0.3 mg/kg), FAAH-selective inhibitors AM3506 (0.3-5.6 mg/kg), URB597 (3.0-5.6 mg/kg), and nonselective FAAH/MGL inhibitor AM4302 (3.0-10.0 mg/kg) revealed that only agonists with CB affinity were able to reduce the rimonabant-like discriminative stimulus effects of withholding daily agonist treatment...SIGNIFICANCE STATEMENT: Despite a growing acceptance that withdrawal symptoms can emerge following the discontinuation of cannabis products, especially in high intake chronic users, there are no FDA-approved pharmacotherapies to assist those seeking treatment. The present studies systematically examined cannabinoid antagonist drug discrimination, a preclinical animal model that is designed to appraise the ability of candidate medications to attenuate the interoceptive effects that accompany abrupt cannabis abstinence.
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