Cannabinoids Block Fat-induced Incretin Release via CB-dependent and CB-independent Pathways in Intestinal Epithelium.

Background And Aims: Glucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity.

Pharmacological inhibition of N-Acylethanolamine acid amidase (NAAA) mitigates intestinal fibrosis through modulation of macrophage activity.

Background And Aims: Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible of acylethanolamides (AEs, e.g.

Chiral Me-2-arachidonoyl Glycerols: The First Potent Endocannabinoid Glyceride Templates with Stability to COX-2.

2-Arachidonoyl glycerol (2-AG) is the principal endogenously produced ligand for the cannabinoid CB1 and CB2 receptors (CBRs). The lack of potent and efficacious 2-AG ligands with resistance against metabolizing enzymes represents a significant void in the armamentarium of research tools available for studying eCB system molecular constituents and their function. Herein we report the first endocannabinoid glyceride templates with remarkably high potency and efficacy at CBRs.

Cannabinoid CB receptors in primary sensory neurons are implicated in CB agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB agonists show therapeutic efficacy without unwanted CB-mediated side effects. The G protein-biased CB receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated.

Virtual Screening of a Chemically Diverse "Superscaffold" Library Enables Ligand Discovery for a Key GPCR Target.

The advent of ultra-large libraries of drug-like compounds has significantly broadened the possibilities in structure-based virtual screening, accelerating the discovery and optimization of high-quality lead chemotypes for diverse clinical targets. Compared to traditional high-throughput screening, which is constrained to libraries of approximately one million compounds, the ultra-large virtual screening approach offers substantial advantages in both cost and time efficiency. By expanding the chemical space with compounds synthesized from easily accessible and reproducible reactions and utilizing a large, diverse set of building blocks, we can enhance both the diversity and quality of the discovered lead chemotypes.

P2X receptor-dependent increase in endocannabinoid 2-arachidonoyl glycerol production by neuronal cells in culture: Dynamics and mechanism.

Background And Purpose: Neurotransmission and neuroinflammation are controlled by local increases in both extracellular ATP and the endocannabinoid 2-arachidonoyl glycerol (2-AG). While it is known that extracellular ATP stimulates 2-AG production in cells in culture, the dynamics and molecular mechanisms that underlie this response remain poorly understood. Detection of real-time changes in eCB levels with the genetically encoded sensor, GRAB, can address this shortfall.

CB Cannabinoid Receptor Agonists Induce Acute Respiratory Depression in Awake Mice.

Recreational use of synthetic cannabinoid agonists (i.e., "Spice" compounds) that target the Cannabinoid Type 1 receptor (CB ) can cause respiratory depression in humans.

Cannabinoid CB receptors in primary sensory neurons are implicated in CB agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB receptors. The G protein-biased CB receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model. However, the specific cell types involved in this phenomenon have never been investigated and whether this therapeutic profile is observed in female mice remains poorly understood.

Correction: Eid et al. 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. 2021, , 866.

The authors wish to make the following changes to the paper [...

Large library docking for cannabinoid-1 receptor agonists with reduced side effects.

Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate.

A Simple Chiral H NMR Method for the Discrimination of ()- and ()-Cannabichromene in Complex Natural Mixtures and Their Effects on TRPA1 Activity.

In recent years, the enantiomeric ratio of cannabichromene (CBC) within the cannabis plant has attracted significant attention. Cannabichromene is one of the well-known cannabinoids found in cannabis, along with THC (tetrahydrocannabinol) and CBD (cannabidiol). Cannabichromene exists as a scalemic mixture, meaning it has two enantiomers, ()-cannabichromene and ()-cannabichromene, with the ratio between these enantiomers varying among different cannabis strains and even within individual plants.

Effects of cannabinoid agonists and antagonists in male rats discriminating the synthetic cannabinoid AM2201.

The synthetic forms of delta-9-tetrahydrocannabinol (Δ-THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ-THC.

Complex 33-beam simulated galactic cosmic radiation exposure impacts cognitive function and prefrontal cortex neurotransmitter networks in male mice.

Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in the prefrontal cortex (PFC) elevated dopamine (DA) but abolished temporal DA responsiveness after acute and chronic GCR exposure.

The neutral CB1 antagonist AM6527 reduces ethanol seeking, binge-like consumption, reinforcing, and withdrawal effects in male and female mice.

Rationale: Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population.

Objective: We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice.

Investigating the Effects of Exogenous and Endogenous 2-Arachidonoylglycerol on Retinal CB1 Cannabinoid Receptors and Reactive Microglia in Naive and Diseased Retina.

The endocannabinoid system (ECS) is a new target for the development of retinal disease therapeutics, whose pathophysiology involves neurodegeneration and neuroinflammation. The endocannabinoid 2-arachidonoylglycerol (2-AG) affects neurons and microglia by activating CB1/CB2 cannabinoid receptors (Rs). The aim of this study was to investigate the effects of 2-AG on the CB1R expression/downregulation and retinal neurons/reactive microglia, when administered repeatedly (4 d), in three different paradigms.

Effects of the CB1 receptor antagonists AM6545 and AM4113 on metabolic syndrome-induced prostatic hyperplasia in rats.

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.

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.

The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million individuals (∼3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ-tetrahydrocannabinol and other plant-derived cannabinoids (phytocannabinoids).

Structural basis for activation of CB1 by an endocannabinoid analog.

Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex.

Cannabis use is associated with low plasma endocannabinoid Anandamide in individuals with psychosis.

Background: Cannabis use suppresses the endocannabinoid system in healthy individuals. However, the association between cannabis use with the endocannabinoid system is understudied in individuals with psychosis despite the high rate of cannabis use in these individuals.

Methods: We enrolled 83 individuals who were admitted to an inpatient psychiatric unit with psychotic presentations, and measured their plasma levels of main endocannabinoids, Anandamide (AEA) and 2-Acylglycerol (2-AG), and endocannabinoid related compounds, Palmitoylethanolamine, and N-oleoylethanolamine.

Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats.

Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710.

Inhibition of triple negative breast cancer-associated inflammation and progression by N- acylethanolamine acid amide hydrolase (NAAA).

Triple-negative breast cancer (TNBC) is associated with high mortality due to the high expression of pro-inflammatory cytokines and lack of targeted therapies. N-acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that promotes inflammatory responses through the deactivation of Palmitoylethanolamide (PEA), an endogenous bioactive lipid mediator. Here, we examined NAAA expression in TNBC cells (MDA-MB-231 and MDA-MB-BrM2 cells) and the effects of NAAA inhibition on TNBC tumor growth, using a selective NAAA inhibitor AM11095 (IC = 20 nM).

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy.

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 - ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2',3'-dideoxycytidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance.