Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant\'s approval, leading to the drug\'s eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA\'s conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.

While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications-and deaths-every year. While an opioid overdose can be reversed by naloxone, there is no analogous treatment for cannabis toxicity. Without an antidote, doctors rely on sedatives, with their own risks, or \'waiting it out\' to treat these patients. We have shown that the canonical synthetic \'designer\' cannabinoids are highly potent CB1 receptor agonists and, as a result, competitive antagonists may struggle to rapidly reverse an overdose due to synthetic cannabinoids. Negative allosteric modulators (NAMs) have the potential to attenuate the effects of synthetic cannabinoids without having to directly compete for binding. We tested a group of CB1 NAMs for their ability to reverse the effects of the canonical synthetic designer cannabinoid JWH018 in vitro in a neuronal model of endogenous cannabinoid signaling and also in vivo. We tested ABD1085, RTICBM189, and PSNCBAM1 in autaptic hippocampal neurons that endogenously express a retrograde CB1-dependent circuit that inhibits neurotransmission. We found that all of these compounds blocked/reversed JWH018, though some proved more potent than others. We then tested whether these compounds could block the effects of JWH018 in vivo, using a test of nociception in mice. We found that only two of these compounds-RTICBM189 and PSNCBAM1-blocked JWH018 when applied in advance. The in vitro potency of a compound did not predict its in vivo potency. PSNCBAM1 proved to be the more potent of the compounds and also reversed the effects of JWH018 when applied afterward, a condition that more closely mimics an overdose situation. Lastly, we found that PSNCBAM1 did not elicit withdrawal after chronic JWH018 treatment. In summary, CB1 NAMs can, in principle, reverse the effects of the canonical synthetic designer cannabinoid JWH018 both in vitro and in vivo, without inducing withdrawal. These findings suggest a novel pharmacological approach to at last provide a tool to counter cannabinoid toxicity.

Cannabinoids have been proposed as therapeutics for pain mitigation. Therefore, the antihyperalgesic effects of a proprietary cannabis-derived mixture, Non-Euphoric Phytocannabinoid Elixir #14 (NEPE14), were examined in a persistent Complete Freund\'s Adjuvant (CFA)-induced model of inflammatory pain. The acute antinociceptive and operant behavioral effects of NEPE14 were then compared with single cannabinoid preparations of Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-THC, the synthetic cannabinoid (-)-CP 55,940 (CP), and cannabidiol (CBD). The THC isomers and CP were also administered with cannabinoid-type-1 receptor (CB1R) antagonist, AM251, and NEPE14 was administered in combination with THC or CP. To induce inflammation, CFA or saline was administered into the paw of male and female Wistar rats. After injections, mechanical hypersensitivity was assessed with Von Frey filaments, and thermal hyperalgesia with a thermal probe. Nine Sprague Dawley rats were also trained to respond under a fixed-ratio 30 schedule for food reinforcers during a 60-min session. Response rates were recorded during the session and warm-water tail-withdrawal latency post session. In CFA-administered rats, mechanical and thermal paw-withdrawal thresholds significantly decreased compared to vehicle, indicating hyperalgesia. Both i.p. (6.6-20.7 ml/kg) and o.m. (30-300 μL) NEPE14 significantly reduced the mechanical and thermal hyperalgesia. In contrast, neither NEPE14 (3.7-20.7 mL/kg i.p., 100-1000 μL o.m.) nor CBD (10-100 mg/kg) significantly decreased response rates or increased tail-withdrawal latency. Acute Δ9-THC, Δ8-THC (1-5.6 mg/kg), and CP (0.032-0.18 mg/kg) significantly and dose-dependently decreased overall response rate and increased tail-withdrawal latency compared to vehicle. AM251 significantly antagonized the rate-decreasing effects of THC, and CP, as well as the antinociceptive effects of CP. Combinations of NEPE14 with Δ9-THC or CP were not significantly different from these cannabinoids alone. In summary, while NEPE14 significantly reduced CFA-induced hyperalgesia, it was more similar to CBD than Δ9-THC, Δ8-THC, and CP for significantly reducing thermal nociception and disrupting conditioned behavior.

Several series of diverse pyrazole-3-carboxamides functionalized with 4-methylamides, 4-methylcarboxylic acids and 4-methyltetrazoles were prepared from the corresponding 4-cyanomethylpyrazoles and investigated as Cannabinoid receptor 1 (CB1) antagonists and inverse agonists with the aim of making compounds with less CNS (Central Nervous System) mediated side-effects compared to rimonabant. The compounds were evaluated and optimized with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers of inflammation and glucose homeostasis, at doses apparently producing negligible brain exposure. TM38837 became the first peripherally restricted CB1 antagonist or inverse agonist to enter clinical trials supporting its lack of CNS effects and it is now believed that the non-CNS mediated efficacy is linked to high liver exposure. This opens opportunities to be explored in other indications such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Note that this is a first-time disclosure of the structure of TM38837 and other structures appearing in literature are not connected with this program.

We have designed orally bioavailable, non-brain-penetrant antagonists of the cannabinoid-1 receptor (CB1R) with a built-in biguanide sensor to mimic 5\'-adenosine monophosphate kinase (AMPK) activation for treating obesity-associated co-morbidities. A series of 3,4-diarylpyrazolines bearing rational pharmacophoric pendants designed to limit brain penetration were synthesized and evaluated in CB1R ligand binding assays and recombinant AMPK assays. The compounds displayed high CB1R binding affinity and potent CB1R antagonist activities and acted as AMPK activators. Select compounds showed good oral exposure, with compounds 36, 38-S, and 39-S showing <5% brain penetrance, attesting to peripheral restriction. In vivo studies of 38-S revealed decreased food intake and body weight reduction in diet-induced obese mice as well as oral in vivo efficacy of 38-S in ameliorating glucose tolerance and insulin resistance. The designed \"cannabinoformin\" four-arm CB1R antagonists could serve as potential leads for treatment of metabolic syndrome disorders with negligible neuropsychiatric side effects.

There is still an unmet need for novel and improved anti-cancer compounds. Nitrogen atoms have heterocyclic ring moieties, which have been shown to have powerful anticancer properties in both natural and synthetic derivatives. Due to their dipole character, hydrogen bonding capacity, rigidity and solubility, 1,2,4-triazoles are particularly effective pharmacophores, interacting with biological receptors with high affinity. Thus, novel 1,2,4-triazole-containing molecular derivatives were synthesized using green chemistry methods, microwave irradiation and ultrasonication, and these methods\' operational simplicity and maximum greener synthetic efficiency with green chemistry metrics calculations will be attractive for academic and industrial research and tested against three distinct human cancer cell lines including PANC1 (pancreatic cancer), DU145 (prostate cancer), MCF7 (breast cancer) and one fibroblast cell line (HDF). Here, we showed that compounds 5e and 5f were similar to CB1 antagonists in structure, binding affinity and poses. In addition, compounds 5e-g decreased the viability of pancreatic and prostate cancer cells, albeit with cytotoxicity to HDF cells. The IC50 values for PANC1 cells were between 5.9 and 7.3 µM for compounds 5e-g. Cell cycle analysis showed that the effect of compounds 5e-g in cancer cell growth was largely due to cell cycle arrest at S-phase. In sum, novel 1,2,4-triazole-containing compounds with anticancer and potent anti-CB1 activity have been developed.Communicated by Ramaswamy H. Sarma.

Metabolic syndrome (MetS) is a combination of metabolic disorders that can predispose individuals to benign prostatic hyperplasia (BPH). The inhibition of the cannabinoid 1 (CB1) receptor has been used to treat metabolic disorders in animal models. This study reports the use of a peripherally restricted CB1 antagonist (AM6545) and a neutral CB1 antagonist (AM4113) to improve MetS-related BPH in rats. Animals were divided into three control groups to receive either a normal rodent diet, AM6545, or AM4113. MetS was induced in the fourth, fifth, and sixth groups using a concentrated fructose solution and high-salt diet delivered as food pellets for eight weeks. The fifth and sixth groups were further given AM6545 or AM4113 for additional four weeks. Body and prostate weights were measured and prostate sections were stained with hematoxylin eosin. Cyclin D1, markers of oxidative stress and inflammation, and levels of the endocannabinoids were recorded. BPH in rats with MetS was confirmed through increased prostate weight and index, as well as histopathology. Treatment with either AM6545 or AM4113 significantly decreased prostate weight, improved prostate histology, and reduced cyclin D1 expression compared with the MetS group. Groups treated with CB1 antagonists experienced reduced lipid peroxidation, recovered glutathione depletion, restored catalase activity, and had lower inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). 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.

The Cannabinoid (CB) signalling cascade is widely located in the human body and is associated with several pathophysiological processes. The endocannabinoid system comprises cannabinoid receptors CB1 and CB2, which belong to G-protein Coupled Receptors (GPCRs). CB1 receptors are primarily located on nerve terminals, prohibiting neurotransmitter release, whereas CB2 are present predominantly on immune cells, causing cytokine release. The activation of CB system contributes to the development of several diseases which might have lethal consequences, such as CNS disorders, cancer, obesity, and psychotic disorders on human health. Clinical evidence revealed that CB1 receptors are associated with CNS ailments such as Alzheimer\'s disease, Huntington\'s disease, and multiple sclerosis, whereas CB2 receptors are primarily connected with immune disorders, pain, inflammation, etc. Therefore, cannabinoid receptors have been proved to be promising targets in therapeutics and drug discovery. Experimental and clinical outcomes have disclosed the success story of CB antagonists, and several research groups have framed newer compounds with the binding potential to these receptors. In the presented review, we have summarized variously reported heterocycles with CB receptor agonistic/antagonistic properties against CNS disorders, cancer, obesity, and other complications. The structural activity relationship aspects have been keenly described along with enzymatic assay data. The specific outcomes of molecular docking studies have also been highlighted to get insights into the binding patterns of the molecules to CB receptors.

Rats re-exposed to an environment previously associated with the onset of shocks evoke a set of conditioned defensive responses in preparation to an eventual flight or fight reaction. Ventromedial prefrontal cortex (vmPFC) is mutually important for controlling the behavioral/physiological consequences of stress exposure and the one\'s ability to satisfactorily undergo spatial navigation. While cholinergic, cannabinergic and glutamatergic/nitrergic neurotransmissions within the vmPFC are shown as important for modulating both behavioral and autonomic defensive responses, there is a gap on how these systems would interact to ultimately coordinate such conditioned reactions. Then, males Wistar rats had guide cannulas bilaterally implanted to allow drugs to be administered in vmPFC 10 min before their re-exposure to the conditioning chamber where three shocks were delivered at the intensity of 0.85 mA for 2 s two days ago. A femoral catheter was implanted for cardiovascular recordings the day before fear retrieval test. It was found that the increment of freezing behavior and autonomic responses induced by vmPFC infusion of neostigmine (acetylcholinesterase inhibitor) were prevented by prior infusion of a transient receptor potential vanilloid type 1 (TRPV1) antagonist, N-methyl-d-aspartate receptor antagonist, neuronal nitric oxide synthase inhibitor, nitric oxide scavenger and soluble guanylate cyclase inhibitor. A type 3 muscarinic receptor antagonist was unable to prevent the boosting in conditioned responses triggered by a TRPV1 agonist and a cannabinoid receptors type 1 antagonist. Altogether, our results suggest that expression of contextual conditioned responses involves a complex set of signaling steps comprising different but complementary neurotransmitter pathways.

The mechanism behind the reinstament of psychostimulant, as a major obstacle in addiction treatment is not fully understood. Controversial data are available in the literature concerning the role of the endocannabinoid (eCB) system in regulating the relapse to psychostimulant addiction in preclinical studies. The current systematic review aims to evaluate eCB modulators\' effect in the reinstatement of commonly abused psychostimulants, including cocaine, amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine. By searching the PubMed, Web of Science, and Scopus databases, studies were selected. Then the studies, quality was evaluated by the SYRCLE risk of bias tool. The results have still been limited to preclinical studies. Thirty-nine articles that employed self-administration and CPP as the most prevalent animal models of addiction were selected. This data indicates that cannabinoid receptor 1 antagonists and some cannabinoid receptor 2 agonists could suppress the reinstatement of cocaine and methamphetamine addiction in a dose-dependent manner. However, only AM251 was efficient to block the reinstatement of 3,4-methylenedioxymethamphetamine. In conclusion, cannabinoid receptor 1 antagonists and some cannabinoid receptor 2 agonists may have curative potential in the relapse of psychostimulant abuse. However, time, dose, and route of administration are crucial factors in their inhibitory impacts.