Acomplia (rimonabant) / Sanofi - LARVOL DELTA

Targeting the CB1 Receptor for Enhanced Obesity Management: Efficacy Comparison of Rimonabant and GLP-1 Receptor Agonist in Diet-Induced Obesity (ECO 2025) - No abstract available

Clinical • Genetic Disorders • Obesity

Mitochondrial Damage and ER Stress in CB1 Receptor Antagonist-Induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells. (PubMed, Neuropharmacology) - "We have found that cell-permeable CB1R antagonists, rimonabant and AM251, induced cell death in human neuroblastoma SH-SY5Y cells under serum-free conditions...These results suggest that CB1R antagonists promote apoptosis via mitochondrial damage and ER stress under serum-free conditions in SH-SY5Y cells. Our findings indicate that while CB1R antagonists may be neuroprotective in certain conditions, they may also pose a neurotoxic risk in environments characterized by cellular stress or nutrient deprivation."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • ATF4

Pharmaco-toxicological effects of the synthetic cannabinoids 4F-ABUTINACA, SDB-005, and JWH-018 in mice. In vitro and in vivo studies. (PubMed, Eur J Pharmacol) - "These findings suggest that these SCs have cannabinoid-specific pharmacological effects and abuse potential, providing robust experimental data to support future regulatory efforts."

Journal • Preclinical • Movement Disorders

Postoperative Weight Loss After Antiobesity Medications and Revision Risk After Joint Replacement. (PubMed, JAMA Netw Open) - "Emulated analyses of a hypothetical target trial were assessed for the association of small-to-moderate (2%-10%) or large (≥10%) weight loss after initiating antiobesity medications (orlistat, sibutramine, glucagon-like peptide-1 receptor agonists, and rimonabant) within 1 year with the risk of 5-year and 10-year revision after initiation of antiobesity medications. In this cohort study using a target trial emulation, a higher proportion of weight loss after initiating antiobesity medications within 1 year was associated with a lower risk of 5-year and 10-year revision among patients with obesity undergoing joint replacement. These results suggest that antiobesity medication use, with relatively safe and sustainable weight loss, may be an effective strategy for improving implant survivorship of hip and knee replacements in the obese population."

Journal • Retrospective data • Genetic Disorders • Musculoskeletal Diseases • Obesity • Orthopedics • Rheumatology

Monlunabant suppresses appetite through a central mechanism. (PubMed, Behav Pharmacol) - "These findings suggest that monlunabant suppresses appetite mainly through antagonism of central CB1 receptors. Consequently, monlunabant and other second-generation CB1 antagonists being developed for obesity may carry a similar risk of adverse psychiatric effects, as previously observed with rimonabant."

Journal • Genetic Disorders • Obesity • Psychiatry

Repeated footshock stress enhances cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1. (PubMed, Physiol Behav) - "However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine self-administration in stress-enhanced rats, similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes."

Journal • Preclinical

Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain. (PubMed, Cannabis Cannabinoid Res) - "The dose-dependent anti-allodynic effects of the MAGL inhibitors (irreversible MAGL inhibitor [JZL184] and selective MAGL inhibitor [MJN110]) and the NSAID diclofenac, as well as the additive potential of combined MAGL and cyclooxygenase (COX) inhibition, were assessed...Similarly, the anti-allodynic effects of the CB2-selective agonist (LY2828360) were tested...The anti-allodynic effects of JZL184 (40 mg/kg) were blocked by pre-treatment of the CB2 antagonist SR144528 (3 mg/kg) but not the CB1-selective antagonist rimonabant (SR141716A; 3 mg/kg), suggesting a CB2-mediated mechanism of anti-allodynia via MAGL inhibition...Finally, HPI per se increased pro-inflammatory cytokine levels, which were unaltered by MAGL inhibition despite the anti-allodynia assessed behaviorally. These data support simultaneously targeting endocannabinoids and COX enzymes as a potential post-operative pain management approach."

Journal • Pain

Dorsomedial Striatum (DMS) CB1R Signaling Promotes Pavlovian Devaluation Sensitivity in Male Long Evans Rats and Reduces DMS Inhibitory Synaptic Transmission in Both Sexes. (PubMed, eNeuro) - "We gave intra-DMS infusions of the CB1R inverse agonist, rimonabant, before satiety-induced outcome devaluation test sessions, where we sated rats on training pellets or home cage chow and tested them in brief nonreinforced PLA sessions...We found that male rats showed decreased sIPSC frequency compared with females and that CB1R activation reduced DMS inhibitory transmission independent of sex. Altogether our results demonstrate that DMS CB1Rs regulate pavlovian devaluation sensitivity and DMS inhibitory synaptic transmission and suggest that basal sex differences in inhibitory synaptic transmission may underly sex differences in DMS function and behavioral flexibility."

Journal • Preclinical

Impact of CB1 receptor antagonism on skeletal muscle hypertrophy and metabolic health: a systematic review of preclinical studies. (PubMed, Hormones (Athens)) - "From these, ten studies were selected, involving 338 rodents, using CB1 antagonists like rimonabant and AM251...This review proposes CB1 receptor antagonism as a promising approach for enhancing muscle hypertrophy and improving metabolic health, with potential applications in treating such conditions as obesity, type 2 diabetes, and sarcopenia. Future research should aim to standardize intervention protocols and explore integrated therapies to fully harness the benefits of CB1 modulation."

Journal • Preclinical • Review • Diabetes • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Sarcopenia • Type 2 Diabetes Mellitus

Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression. (PubMed, Pharmacol Res) - "Altogether, our results indicate that S-KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry • GPR55

The CB1 antagonist Rimonabant improves muscle regeneration and remodels the inflammatory and endocannabinoid profile upon injury in male mice. (PubMed, Life Sci) - "The present study investigated the effect of the CB1 antagonist Rimonabant (10 mg/kg/d) on functional (5 days post-cardiotoxin injury; 5DPI) and molecular muscle responses (3DPI and 7DPI) in mice. In addition, Rimonabant restored the injury-induced (inflammatory) lipid profile to a large extent, including oxygenated fatty acids, unsaturated fatty acids and endocannabinoids such as 2-arachidonoyl glycerol and palmitoylethanolamide. Altogether, these data show that the endocannabinoid system might be a novel therapeutic target to improve muscle regeneration, which is relevant for age- and disease-related muscle degeneration."

Journal • Preclinical • Fibrosis • Inflammation • CASP3 • CD80 • PAX7

Endocannabinoid involvement in beneficial effects of caloric restriction in a rodent model of comorbid depression and epilepsy. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Male rats restricted to approximately 80 % of their daily food intake for an acute 24-h period showed elevated struggling behavior in the Porsolt (Forced) Swim Test and increased latency to pilocarpine-induced seizure; this same caloric restriction yielded a significant increase in hippocampal anandamide levels compared to ad lib rats. Administration of 1 mg/kg SR141716 alongside an acute caloric restriction in male rats blocked the antidepressant-like effects of caloric restriction but did not affect seizure responses. Combined, these results suggest caloric restriction may be both safe and modestly effective in benefitting depression- and epilepsy-related behaviors in male SwLo rats, and that the endocannabinoid system may be a promising target for treating this comorbidity."

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

A Sex-Dependent Cannabinoid CB1 Receptor Role in Circadian Tearing of the Mouse. (PubMed, Invest Ophthalmol Vis Sci) - "This increased tearing is mimicked by the CB1 antagonist SR141716 (4 mg/kg, intraperitoneally [IP]), suggesting that tonic CB1 activation dampens female circadian tearing...Mice have a sex-dependent circadian cycle of tearing. The endogenous cannabinoid signaling system appears to mediate some circadian effects, albeit in a sex-dependent manner and via distinct cellular targets."

Journal • Preclinical

Beyond the Scale: Exploring the Endocannabinoid System's Impact on Obesity. (PubMed, Curr Diab Rep) - "While therapeutic approaches targeting the ECS, particularly CB1 receptor antagonism, have shown potential in managing obesity, the review acknowledges the challenges posed by central nervous system side effects in earlier treatments like rimonabant. However, recent advancements in peripherally restricted CB1 antagonists offer renewed hope for safer and more effective obesity treatments. The review concludes by addressing future research directions and therapeutic strategies to combat this global health challenge."

Journal • Review • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • LEP

Rimota-Gd: Paramagnetic Probe for In Vivo MRI Studies of the Cannabinoid 1 Receptor Distribution in the Mouse Brain. (PubMed, ACS Chem Neurosci) - "By chemically conjugating the CB1 antagonist rimonabant acid to a gadolinium chelator, we obtained the paramagnetic probe Rimota-Gd...We used Rimota-Gd to investigate the spatial distribution of CB1 across the mouse brain and compared the results with an investigation using the PET radioligand [18F]MK-9470. Rimota-Gd opens the door for in vivo MRI imaging of CB1 and provides a roadmap for the study of other receptors by whole-brain images with high spatial and temporal resolution."

Journal • Preclinical • CNS Disorders • Pain • Psychiatry

Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal. (PubMed, Cells) - "Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence...Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo-mesencephalic circuit are implicated in the mechanisms underlying substance use disorders."

Journal • CNS Disorders

Induction and Maintenance Regimens With CB1 Inverse Agonist CRB-913 and Semaglutide in DIO Mice (OBESITY WEEK 2024) - "We previously reported that CRB-913 demonstrated reduced brain levels (25-fold lower brain Cmax and 9.5-fold lower brain AUClast) than the first-generation CB1 IA rimonabant, at equivalent doses (10 mg/kg) in mice...Moreover, treatment with CRB-913 in combination with the incretin analogs liraglutide, semaglutide or tirzepatide resulted in additive effects on weight loss as well as improved liver function and reduced liver fat content... CRB-913 provides a potentially efficacious treatment via targeting of the CB1 pathway for achieving as well as maintaining weight loss. This data provides utility in crafting a clinical trial strategy and assessing how such a drug could be used in clinical practice."

Preclinical • Genetic Disorders • Obesity

Cannabinoid regulation of sex-dependent murine odorant-stimulated salivation. (PubMed, Sci Rep) - "In mice, the CB1 antagonist SR141716 (4 mg/kg, IP) prevented a previously learned salivary response to peanut butter...In summary, we find a novel sex-dependence in responses to a subset of food-related odorant cues and that cannabinoid receptors regulate some of these responses. We propose that CB1 receptors act at the parotid gland to inhibit stimulated salivation but also in the olfactory system, where functional CB1 receptors are required for salivary responses to specific appetitive odors."

Journal • Preclinical • Xerostomia

The APJ Agonist Azelaprag Improves Weight Loss and Body Composition in DIO Mice on a CB1 Antagonist (OBESITY WEEK 2024) - "Addition of azelaprag to rimonabant significantly increased weight loss and improved body composition relative to monotherapy with the CB1 antagonist. Our data suggest that the combination of CB1 inhibition and apelin pathway activation results in a synergistic change in metabolic processes. These findings highlight the potential of azelaprag as a therapeutic candidate in combination approaches to treating obesity and related metabolic conditions."

Preclinical • Genetic Disorders • Obesity

Seventeen Years Since Rimonabant's Downfall: Reassessing Its Suicidality Risk Profile (OBESITY WEEK 2024) - "We conclude that the data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality. We identify the usage by FDA of the (now abandoned) post-hoc analysis done by means of C-CASA as a potential source of this misadjudication."

Genetic Disorders • Obesity

Pleasant Odor Decreases Mouse Anxiety-like Behaviors by Regulating Hippocampal Endocannabinoid Signaling. (PubMed, Int J Mol Sci) - "Further studies found that selective inhibition of endocannabinoid signaling by injecting rimonabant abolished the activation of DGCs and the anxiolytic effect induced by linalool or 2-phenylethanol. Together, these results uncovered a novel mechanism by which linalool or 2-phenylethanol decreases mouse anxiety-like behaviors and increases DG activity likely through activating hippocampal retrograde endocannabinoid signaling."

Journal • Preclinical • CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry

NOVEL CANNABINOID -1 RECEPTOR (CB1R) ANTAGONIST GENISTEIN RESTORES HEPATIC MICROVASCULAR FUNCTION, REDUCES LIVER FIBROSIS AND AMELIORATES PORTAL HYPERTENSION (AASLD 2024) - "Insilico, findings confirmed the SAR and enhanced bioavailability in comparison to rimonabant... Genistein significantly reduces portal pressure, collagen deposition and prevents HSC activation in cirrhosis animals. It restores the endothelial function, most importantly, without breaching blood brain barrier. Genistein appears an effective novel therapy for cirrhosis by mitigating portal hypertension without causing any neurological side-effects and merits clinical validation."

Cardiovascular • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Portal Hypertension • CD31 • COL1A1 • IL6 • NOS3 • PECAM1 • TGFB1 • TNFA

PERIPHERAL BLOCKADE OF CB1 SIGNALING IMPROVES LIVER FIBROSIS (AASLD 2024) - "Unfortunately, the first-in-class brain-penetrant CB1R antagonist Rimonabant, initially approved for the management of obesity and related cardiometabolic risks, was withdrawn because of CNS-mediated neuropsychiatric side effects... This study provides genetic foundational and proof-of-concept studies indicating that peripheral CB1 antagonists (sparing the CNS and the brain) have potential therapeutic applications in multiple liver diseases. However, deletion of CB1 specifically in HSC did not have a protective effect in our models of liver disease."

Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Psychiatry • MX1

Assessment of pharmacological effects and abuse potential of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 in mice. (PubMed, Psychopharmacology (Berl)) - "The results of this study indicated that these SCs possess cannabinoid-specific pharmacological effects and abuse potential, which provides substantial experimental data to support the future regulation of these substances."

Journal • Preclinical • Movement Disorders

New peripherally-restricted CB1 receptor antagonists, PMG-505-010 and -013 ameliorate obesity-associated NAFLD and fibrosis. (PubMed, Biomed Pharmacother) - "In this study, we synthesized PMG-505-010 and PMG-505-013 as peripherally restricted CB1 receptor antagonists by modifying rimonabant to minimize BBB penetration...Notably, these compounds inhibited hepatic fibrosis by reducing extracellular matrix (ECM) deposition and altering fibrosis-related gene and protein expressions. In conclusion, PMG-505-010 and PMG-505-013 hold promise for treating obesity-related liver diseases, including NAFLD and fibrosis, through selective peripheral CB1R targeting, potentially avoiding CNS-related side effects seen with earlier CB1R antagonists."

Journal • Dyslipidemia • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Psychiatry