AM6545 / MAKScientific, Amakos Biotherap - LARVOL DELTA

Acetaminophen alters endogenous lipid signaling and attenuates pathological pain through a mechanism requiring diacylglycerol lipase, monoacylglycerol lipase and cannabinoid CB1 receptors in mice. (PubMed, Neuropharmacology) - "Global (rimonabant, AM251) but not peripherally restricted (AM6545) cannabinoid receptor antagonists prevented APAP-induced analgesia. In addition, APAP reduced up to 39% of signaling lipids detected in the targeted screen in CFA-treated subjects in a tissue-dependent manner. These observations suggest that APAP plays a wider role in endogenous lipid signaling than previously hypothesized and provides novel insight into mechanisms of action."

Journal • Preclinical • Immunology • Pain

Short Communication: The Peripheral Cannabinoid CB1 Receptor Antagonist AM6545 Modifies Cardiovascular Effects of Endocannabinoids in DOCA-Salt Rats. (PubMed, Int J Mol Sci) - "For this purpose, we applied methanandamide (MethAEA), a stable analogue of anandamide, and URB597, an inhibitor of its degradation, in urethane-anesthetized animals. In conclusion, AM6545 modifies the cardiovascular effects of endocannabinoids in hypertension in a model-dependent manner. The cardiovascular effects of CB1R antagonists should be carefully evaluated when assessing their potential therapeutic significance, as they may unmask an increase in BP."

Journal • Preclinical • Anesthesia • Cardiovascular • Hypertension • Hypotension

Inhibition of peripheral CB1 receptors modulates food intake and metabolic efficiency in obesity independently of the gut-brain vagal axis. (PubMed, Br J Pharmacol) - "Our findings revealed a dual-mechanism model: vagal pathways mediated brainstem engagement, while hypothalamic recruitment and metabolic improvements occurred via vagal-independent signalling. Thus, peripherally-restricted CB1 receptor antagonists indirectly engage central homeostatic circuits, supporting their therapeutic potential for obesity even in conditions with impaired vagal signalling."

Journal • Endocrine Cancer • Genetic Disorders • Obesity • Psychiatry

Taurine attenuates lipid accumulation via the eCB-CB1 axis: evidence from adipose metabolomics in HFD-fed mice and 3D adipocyte spheroids. (PubMed, Front Nutr) - "Additionally, 3T3-L1 adipocyte spheroids were treated with taurine (0-0.5 mM), either alone or in combination with the cannabinoid receptor type 1 (CB1) agonist CP55940 or antagonist AM6545, to assess its effects on lipid accumulation and underlying mechanisms...Moreover, taurine suppressed lipid accumulation by inhibiting CB1 signaling, a mechanism supported by downregulation of lipogenic genes (including Srebf1, Acaca, Cd36, and Pparg) and upregulation of lipolytic genes (including Pnpla2, Lipe, and Ppargc1a). Collectively, our findings demonstrate that taurine exerts its anti-obesity effects partially via modulation of eCB-CB1 signaling, coordinately inhibiting lipogenesis and promoting lipolysis, thereby highlighting its therapeutic potential for obesity management."

Journal • Preclinical • Genetic Disorders • Metabolic Disorders • Obesity • CD36 • PPARG • PPARGC1A • SCARB1

Combined CB1 antagonist AM6545 and NOP agonist SCH221510 worsen DSS-induced colitis in mice. (PubMed, Adv Clin Exp Med) - "Our study offers novel insights into the interaction between the ECS and the NOP receptor, which may inform the development of new therapeutic strategies for inflammatory conditions such as colitis."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid receptors and the enzyme diacylglycerol lipase in mice. (PubMed, bioRxiv) - "Pharmacological specificity was assessed using global (Rimonabant, AM251) and peripherally restricted (AM6545) CB1 antagonists. Our studies demonstrate that the analgesic effects of APAP observed in mouse models of pathological pain require both DAGL and CB1 activation. Our findings support a potential mechanism of APAP-induced analgesic action involving the enzyme DAGL and CB1 receptors."

Journal • Preclinical • Immunology • Inflammation • Pain

Sub-chronic administration of AM6545 enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice. (PubMed, Br J Pharmacol) - "Our results showed that repeated administration of AM6545 contributed to the modulation of memory persistence, executive function and hippocampal synaptic plasticity in mice, further indicating that peripheral CB1 receptors could act as a target for a novel class of nootropic compounds."

Journal • Preclinical • BDNF • CA3 • NGF

CB1 Cannabinoid Receptor Agonists Induce Acute Respiratory Depression in Awake Mice. (PubMed, Pharmacol Res) - "Respiratory suppressive effects were fully blocked by the CB1 antagonist AM251, were minimally impacted by the peripherally-restricted CB1 antagonist AM6545, and occurred at doses lower than those that produce cardinal behavioral signs of CB1 activation. Using RNAscope in situ hybridization, we also demonstrated extensive coexpression of Cnr1 (encoding the CB1 receptor) and Oprm1 (encoding the µ-opioid receptor) mRNA in respiratory cells in the medullary pre-Bötzinger complex, a critical nucleus of respiratory control. Our results show that mRNA for CB1 is present in respiratory cells in a medullary brain region essential for breathing and demonstrate that cannabinoids produce respiratory suppression via activation of central CB1 receptors."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Psychiatry • Respiratory Diseases • CNR1 • OPRM1

Cannabinoids Block Fat-induced Incretin Release via CB1-dependent and CB1-independent Pathways in Intestinal Epithelium. (PubMed, Gastro Hep Adv) - "We treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1-/-) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9 tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545...In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells. These results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

The molecular signature of the peripheral cannabinoid receptor 1 antagonist AM6545 in adipose, liver and muscle tissue. (PubMed, Toxicol Appl Pharmacol) - "These data indicate that acute CB1 antagonism is effective to induce phosphorylation events of signaling cascades and metabolic markers in metabolic tissues of healthy, lean mice within a 90-min time window. The observed adaptations to AM6545 treatment do not fully align with earlier in vitro and in vivo findings, which could be ascribed to differences in cell type, exposure intensity (dose and time), health status and species."

Journal • Metabolic Disorders • mTOR

Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid recepto (IASP 2024) - "Pharmacological specificity was assessed using both global (rimonabant, AM251) and peripherally restricted (AM6545) cannabinoid type 1 receptor (CB1) antagonists. Antinociceptive effects of acetaminophen observed in mouse models of persistent pain require both DAGL alpha and CB1 activation. Our findings support a potential mechanism of acetaminophen-induced analgesic action involving the enzyme DAGL."

Immunology • Pain

Cholinergic neurotransmission controls orexigenic endocannabinoid signaling in the gut in diet-induced obesity. (PubMed, J Neurosci) - "Moreover, the peripherally-restricted mAChR antagonist, methylhomatropine bromide, and the peripherally-restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs...This effect was absent in mice conditionally lacking CB1Rs in the intestinal epithelium. These findings expand our understanding of the complex pathophysiology associated with obesity and mechanisms of brain-gut-brain signaling."

Journal • Gastrointestinal Disorder • Genetic Disorders • Obesity

Effects of cannabinoid agonists and antagonists in male rats discriminating the synthetic cannabinoid AM2201. (PubMed, Eur J Pharmacol) - "The synthetic forms of delta-9-tetrahydrocannabinol (Δ-THC), dronabinol or nabilone, have been approved to treat several indications...After establishing AM2201's discriminative-stimulus effects, pretreatment tests with the CB antagonist/inverse agonist rimonabant blocked AM2201's effects, whereas the peripherally-restricted antagonist AM6545 had no effect. Next, the generalization profiles of AM411 and AM4089 with CB full agonists (JWH-018, CP-55,940, AM8936), partial agonist (Δ-THC), and non-cannabinoids (fentanyl, atropine) were compared...All CB drugs were more potent than Δ-THC and correlation analysis confirmed that the relative behavioral potencies of CBs corresponded strongly with their relative affinities at the CB but not CB receptors. Together, our results further demonstrate that AM411 and AM4089 exhibit better pharmacological profiles compared to Δ-THC, in that they are more potent and display in vivo partial agonist-like actions that are centrally..."

Journal • Preclinical

THE POTENTIAL OVERLAP BETWEEN CANNABINOID AND NOCICEPTIN SIGNALING AND ITS ROLE IN INTESTINAL INFLAMMATION IN A MOUSE MODEL AND HUMAN SAMPLES (UEGW 2023) - "3 mg/kg), CB1 antagonist (AM 6545, 3mg/kg) or CB2 antagonist (AM 630, 5mg/kg) were given intraperitoneally, twice daily, alone or in combination... We obtained promising results suggesting the existence of cross-talk between the CB and NOP receptors. Fully elucidating this phenomenon could aid in developing novel treatment options for IBD patients."

Preclinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL6 • MPO • STAT3

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

The cannabinoid receptor 1 antagonist AM6545 stimulates the Akt-mTOR axis and in vivo muscle protein synthesis in a dexamethasone-induced muscle atrophy model. (PubMed, Mol Cell Endocrinol) - "The present study for the first time shows that the CB antagonist AM6545 can upregulate the Akt-mTOR axis and in vivo muscle protein synthesis. However, future work applying genetic approaches should further uncover the signaling pathways via which AM6545 enhances muscle anabolism."

Journal • Preclinical • Muscular Atrophy

THE OVERLAP BETWEEN CANNABINOID AND NOCICEPTIN SIGNALING AND ITS ROLE IN INTESTINAL INFLAMMATION – A PILOT STUDY (UEGW 2022) - "3 mg/kg), CB1 antagonist (AM 6545, 3mg/kg) or CB2 antagonist (AM 630, 5mg/kg) were given intracolonically, twice daily, alone or in combination... We obtained promising results suggesting the existence of cross-talk between the CB and NOP receptors. Fully elucidating this phenomenon could aid in developing novel treatment options for patients with IBD based on the modulation of activity of ECS or NOP receptors."

Clinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • MPO

Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism. (PubMed, Neuropsychopharmacology) - "In agreement, intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory."

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Role of CB receptors in the acute regulation of small intestinal permeability: Effects of high-fat diet. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "Neither the CB/CB agonist CP55,940 nor the CB neutral antagonist AM6545 altered the flux of 4Kda FITC dextran (FD4) across the jejunum or ileum of chow-fed mice...Neither ligand altered the expression of ZO-1. Our data suggest that CB receptor on the intestinal epithelium regulates tight junction protein expression and restores barrier function when it is increased following exposure to a HFD for 2 weeks."

Journal • Gastrointestinal Disorder • TJP1

Ghrelin-Ghrelin receptor (GSHR) pathway via endocannabinoid signal affects the expression of NPY to promote the food intake of Siberian sturgeon (Acipenser baerii). (PubMed, Horm Behav) - "The results showed that AM6545 (CB1 peripheral restricted antagonist) failed to affect the orexigenic effect of Ghrelin and the expression pattern of NPY mRNA in the telencephalon. While in the diencephalon, the increase of food intake and NPY mRNA expression induced by Ghrelin was completely reversed by Rimonabant (CB1 global antagonist). These results indicate Ghrelin-GSHR pathway promotes the food intake of Siberian sturgeon by inducing the expression of NPY in the diencephalon, and the stimulating effect will be reversed by cannabinoid receptor antagonism. This study provides a foundation for understanding the pathways Ghrelin and CB1 signals in appetite regulation of the teleost."

Journal • CNS Disorders

Role of primary sensory neurone cannabinoid type-1 receptors in pain and the analgesic effects of the peripherally acting agonist CB-13 in mice. (PubMed, Br J Anaesth) - "CBR signalling in primary sensory neurones did not inhibit nociceptive or inflammatory pain, or the intrinsic excitability of nociceptive neurones. However, peripheral CBRs are important for the analgesic effects of systemically administered CB-13. In addition, HVA-I inhibition appears to be a key ionic mechanism for CB-13-induced pain inhibition. Thus, peripherally restricted CBR agonists could have utility for pain treatment."

Journal • Preclinical • Immunology • Inflammation • Pain

[VIRTUAL] The Role of Peripheral Cannabinoid (CB)-1 Receptors in Inflammatory Pain (IASP 2021) - "CB-13 (10 nM) significantly inhibited high-voltage activated (HVA) calcium currents (ICa) in small-diameter WT DRG neurons, which was attenuated by CB1R antagonist, AM6545 (10 nM), and was unaffected by peripheral MOR knockout...Morphine (5 mg/kg, s.c.) analgesia was unaffected in CB1R cKO mice. The present results suggest that endogenous CB1R signaling in DRG neurons does not contribute to a tonic inhibition of nociceptive pain thresholds... The present results suggest that endogenous CB1R signaling in DRG neurons does not contribute to a tonic inhibition of nociceptive pain thresholds. However, pain inhibition produced by systemic CB-13 administration in vivo is mediated by CB1Rs on DRG neurons, and is not affected by peripheral MOR signaling. Additionally, CB1R signaling initiated by CB-13 application produced significant HVA-ICa reductions in small DRG neurons, which potentially reduces overall nociceptive signal input to the spinal cord and represents a key ionic..."

Pain

Cannabinoid Receptor Subtype-1 Regulates Allergic Airway Eosinophilia During Lung Helminth Infection. (PubMed, Cannabis Cannabinoid Res) - " Hemorrhaging of lung tissue in mice infected with N. brasiliensis was exacerbated by inhibiting peripheral cannabinoid receptor subtype-1 (CBRs) with the peripherally restricted CBR antagonist, AM6545... Roles for the eCB system in Th2 immune responses are not well understood; however, increases in its activity in response to infection suggest an immunomodulatory role. Moreover, these findings suggest a role for eCB signaling at CBRs but not cannabinoid receptor subtypes-2 in the resolution of Th2 inflammatory responses, which become host destructive over time."

Journal • Eosinophilia • Fibrosis • Hematological Disorders • Immune Modulation • Immunology • Infectious Disease • Inflammation • Respiratory Diseases

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

Peripherally restricted cannabinoid type 1 receptor (CB1R) antagonist, AM6545, potentiates stress-induced hypothalamic-pituitary-adrenal axis activation via a non-CB1R mechanism. (PubMed, Endocrine) - No abstract available

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