AM6545 / MAKScientific, Amakos Biotherap - LARVOL DELTA

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."

Journal

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

Journal

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

Involvement of cannabinoid type 1 receptor in fasting-induced analgesia. (PubMed, Mol Pain) - "Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects."

Journal • Gastrointestinal Disorder • Pain

Reversal of Diet-induced Hepatic Steatosis by Peripheral CB1 Receptor Blockade in Mice is p53/miRNA-22/SIRT1/PPARα Dependent. (PubMed, Mol Metab) - "We provide a strong evidence for a functional role of the p53/miR-22/SIRT1/PPARα signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CBR blockade."

Journal • Preclinical • Genetic Disorders • Hepatology • Liver Failure • Metabolic Disorders • Obesity • SIRT1

A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided. (PubMed, Int J Mol Sci) - "The brain- and peripheral-cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been shown to induce weight loss and improve glucose homeostasis...Given the adverse side-effects of brain-penetrance with RIM, in this study we aimed to determine the site of action for a non-brain-penetrating CB1R antagonist AM6545...Using a lipolysis inhibitor during real-time OCR measurements, we determined that the impact of CB1R antagonism on adipocytes is driven by increased lipolysis. Thus, our data suggest the direct role of CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of focus on peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and T2D."

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

Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System. (PubMed, Molecules) - "CB antagonism with AM6545 or CB agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain."

Journal • Preclinical • Hepatology • Immunology • Liver Failure • CASP3

Endocannabinoid regulation of homeostatic feeding and stress-induced alterations in food intake in male rats. (PubMed, Br J Pharmacol) - "The current study reveals diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress."

Journal • Preclinical • Anorexia • Gastrointestinal Disorder