scholarly journals Computer modeling of Cannabinoid receptor type 1

2018 ◽  
Vol 16 ◽  
pp. 02008
Author(s):  
Fatima Sapundzhi ◽  
Tatyana Dzimbova ◽  
Nevena Pencheva ◽  
Peter Milanov
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Scoring Function ◽  
Docking Studies ◽  
Cb1 Receptors ◽  
Important Class ◽  
Pain Sensation ◽  
Physiological Processes ◽  
Selective Ligands

Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE). They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

scholarly journals Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities

2019 ◽  
Vol 20 (23) ◽  
pp. 5874 ◽  
Author(s):  
Hryhorowicz ◽  
Kaczmarek-Ryś ◽  
Andrzejewska ◽  
Staszak ◽  
Hryhorowicz ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Memory Loss ◽  
Allosteric Modulation ◽  
Site Directed Mutagenesis ◽  
New Horizons ◽  
X Ray Crystallography ◽  
Physiological Processes ◽  
G Protein Coupled

The cannabinoid receptor type 1 (CB1R), a G protein-coupled receptor (GPCR), plays an essential role in the control of many physiological processes such as hunger, memory loss, gastrointestinal activity, catalepsy, fear, depression, and chronic pain. Therefore, it is an attractive target for drug discovery to manage pain, neurodegenerative disorders, obesity, and substance abuse. However, the psychoactive adverse effects, generated by CB1R activation in the brain, limit the use of the orthosteric CB1R ligands as drugs. The discovery of CB1R allosteric modulators during the last decade provided new tools to target the CB1R. Moreover, application of the site-directed mutagenesis in combination with advanced physical methods, especially X-ray crystallography and computational modeling, has opened new horizons for understanding the complexity of the structure, function, and activity of cannabinoid receptors. In this paper, we present the latest advances in research on the CB1R, its allosteric modulation and allosteric ligands, and their translational potential. We focused on structural essentials of the cannabinoid 1 receptor- ligand (drug) interactions, as well as modes of CB1R signaling regulation.

scholarly journals Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

2020 ◽  
Vol 21 (20) ◽  
pp. 7693
Author(s):  
Dhanush Haspula ◽  
Michelle A. Clark
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Inflammatory Diseases ◽  
Endocannabinoid System ◽  
Future Directions ◽  
The Past ◽  
Health And Disease ◽  
Made In

The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.

The Cannabinoid Agonist WIN55,212-2 Suppresses Opioid-induced Emesis in Ferrets

2001 ◽  
Vol 94 (5) ◽  
pp. 882-887 ◽  
Author(s):  
Isabelle I. Simoneau ◽  
Maged S. Hamza ◽  
Heriberto P. Mata ◽  
Erin M. Siegel ◽  
Todd W. Vanderah ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Cb1 Receptors ◽  
Cb2 Receptor ◽  
Selective Antagonist ◽  
Receptor Agonists ◽  
Antiemetic Activity ◽  
The Central Nervous System ◽  
Cannabinoid Agonist

Background Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis. This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting. Methods Twelve male ferrets were used. They weighed 1.2-1.6 kg at the beginning and 1.8-2.3 kg at the end of the experiments. All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted at 5-min intervals for 30 min after morphine injection. Results Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous administration of naloxone prevented morphine-induced retching and vomiting. WIN55,212-2 dose-dependently reduced retching and vomiting. The ED50 was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decreased by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-selective antagonist, did not. Conclusions These results demonstrate that WIN55,212-2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN55,212-2 occurs at CB1 receptors. This is consistent with findings that CB1 receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated.

scholarly journals Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats

2017 ◽  
Vol 312 (3) ◽  
pp. F482-F488 ◽  
Author(s):  
Xuewen Jiang ◽  
Michelle Yu ◽  
Jamie Uy ◽  
Thomas W. Fuller ◽  
Cameron Jones ◽  
...  
Keyword(s):  
Nerve Stimulation ◽  
Cannabinoid Receptor ◽  
Bladder Capacity ◽  
Intrathecal Administration ◽  
Saline Control ◽  
Cb1 Receptors ◽  
Pudendal Neuromodulation ◽  
Bladder Disorders

The role of cannabinoid type 1 (CB1) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical infusion of 0.5% acetic acid (AA) was determined in α-chloralose anesthetized cats. AA irritation significantly ( P < 0.01) reduced bladder capacity to 36.6 ± 4.8% of saline control capacity. Tibial nerve stimulation (TNS) at two or four times threshold (2T or 4T) intensity for inducing toe movement inhibited bladder overactivity and significantly ( P < 0.01) increased bladder capacity to 69.2 ± 9.7 and 79.5 ± 7.2% of saline control, respectively. AM 251 (a CB1 receptor antagonist) administered intravenously at 0.03 or 0.1 mg/kg significantly ( P < 0.05) reduced the inhibition induced by 2T or 4T TNS, respectively, without changing the prestimulation bladder capacity. However, intrathecal administration of AM 251 (0.03 mg) to L7 spinal segment had no effect on TNS inhibition. Pudendal nerve stimulation (PNS) also inhibited bladder overactivity induced by AA irritation, but AM 251 at 0.01–1 mg/kg iv had no effect on PNS inhibition or the prestimulation bladder capacity. These results indicate that CB1 receptors play an important role in tibial but not pudendal neuromodulation of bladder overactivity and the site of action is not within the lumbar L7 spinal cord. Identification of neurotransmitters involved in TNS or PNS inhibition of bladder overactivity is important for understanding the mechanisms of action underlying clinical application of neuromodulation therapies for bladder disorders.

scholarly journals Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice

2020 ◽  
Vol 4 (6) ◽  
pp. 382-389
Author(s):  
V.A. Dudareva ◽  
◽  
M.L. Maksimov ◽  
I.G. Djadikova ◽  
A.A. Zveginceva ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Medical Society ◽  
Cannabinoid Receptor 1 ◽  
Peripheral Tissues ◽  
Theory To Practice

Obesity that results in various metabolic disorders is one of the central concerns of modern healthcare system. Only 4% to 5% of patients with metabolic syndrome achieve favorable outcomes without any additional pharmacotherapy. Therefore, many patients require weight-loss drugs in addition to non-pharmacological treatments. The endocannabinoid system and the drugs that affect its functions receive a widespread attention of medical society due to its effects on behavioral and cerebral functions and its potential use as a therapeutic “target” in various peripheral and neurological psychiatric disorders. Among known to date cannabinoid receptors, type 1 receptors play a role in the development of obesity. It was demonstrated that the blockade of these receptors in the hypothalamus reduces appetite, inhibits adipocyte activation in peripheral tissues, prevents lipogenesis, and increases the level of adiponectin. The result is the decreased levels of atherogenic lipoproteins and improved insulin resistance. This article addresses the results of fundamental and clinical studies on Dietressa, a drug composed of affine-purified antibodies to cannabinoid receptor 1. Case report of a patient with obesity that analyzes pharmaceutical and non-pharmaceutical treatment approaches is described.KEYWORDS: obesity, metabolic syndrome, diet, endocannabinoid system, cannabinoids, cannabinoid receptors, affine-purified antibodies.FOR CITATION: Dudareva V.A., Maksimov M.L., Djadikova I.G. et al. Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice. Russian Medical Inquiry. 2020;4(6):382–389. DOI: 10.32364/2587-6821-2020-4-6-382-389.

scholarly journals Putative Activation of the CB1 Cannabinoid Receptors Prevents Anxiety-Like Behavior, Oxidative Stress, and GABA Decrease in the Brain of Zebrafish Submitted to Acute Restraint Stress

2021 ◽  
Vol 14 ◽  
Author(s):  
Waldo Lucas Luz ◽  
Mateus Santos-Silva ◽  
Patrick Bruno Cardoso ◽  
Nadyme Assad ◽  
Edinaldo Rogério da Silva Moraes ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Restraint Stress ◽  
Cannabinoid Receptors ◽  
Acute Stress ◽  
Control Treatment ◽  
Cb1 Receptors ◽  
Acute Restraint Stress ◽  
Gaba Content ◽  
The Brain

Anxiety disorder is a well-recognized condition observed in subjects submitted to acute stress. Although the brain mechanisms underlying this disorder remain unclear, the available evidence indicates that oxidative stress and GABAergic dysfunction mediate the generation of stress-induced anxiety. Cannabinoids are known to be efficient modulators of behavior, given that the activation of the cannabinoid receptors type-1 (CB1 receptors) induces anxiolytic-like effects in animal models. In the present study, we aimed to describe the effects of the stimulation of the CB1 receptors on anxiety-like behavior, oxidative stress, and the GABA content of the brains of zebrafish submitted to acute restraint stress (ARS). The animals submitted to the ARS protocol presented evident anxiety-like behavior with increased lipid peroxidation in the brain tissue. The evaluation of the levels of GABA in the zebrafish telencephalon presented decreased levels of GABA in the ARS group in comparison with the control. Treatment with ACEA, a specific CB1 receptor agonist, prevented ARS-induced anxiety-like behavior and oxidative stress in the zebrafish brain. ACEA treatment also prevented a decrease in GABA in the telencephalon of the animals submitted to the ARS protocol. Overall, these preclinical data strongly suggest that the CB1 receptors represent a potential target for the development of the treatment of anxiety disorders elicited by acute stress.

scholarly journals Interference with the Cannabinoid Receptor CB1R Results in Miswiring of GnRH3 and AgRP1 Axons in Zebrafish Embryos

2019 ◽  
Vol 21 (1) ◽  
pp. 168 ◽  
Author(s):  
Giulia Zuccarini ◽  
Ilaria D’Atri ◽  
Erika Cottone ◽  
Ken Mackie ◽  
Inbal Shainer ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Zebrafish Embryos ◽  
Low Doses ◽  
Axonal Projections ◽  
Embryonic Exposure ◽  
G Protein Coupled ◽  
Bioinformatic Approach

The G protein-coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and their endocannabinoid (eCBs) ligands, have been implicated in several aspects of brain wiring during development. Here we aim to assess whether interfering with CB1R affects development, neuritogenesis and pathfinding of GnRH and AgRP neurons, forebrain neurons that control respectively reproduction and appetite. We pharmacologically and genetically interfered with CB1R in zebrafish strains with fluorescently labeled GnRH3 and the AgRP1 neurons. By applying CB1R antagonists we observed a reduced number of GnRH3 neurons, fiber misrouting and altered fasciculation. Similar phenotypes were observed by CB1R knockdown. Interfering with CB1R also resulted in a reduced number, misrouting and poor fasciculation of the AgRP1 neuron’s axonal projections. Using a bioinformatic approach followed by qPCR validation, we have attempted to link CB1R functions with known guidance and fasciculation proteins. The search identified stathmin-2, a protein controlling microtubule dynamics, previously demonstrated to be coexpressed with CB1R and now shown to be downregulated upon interference with CB1R in zebrafish. Together, these results raise the likely possibility that embryonic exposure to low doses of CB1R-interfering compounds could impact on the development of the neuroendocrine systems controlling sexual maturation, reproduction and food intake.

scholarly journals Functional diversity on synaptic plasticity mediated by endocannabinoids

2012 ◽  
Vol 367 (1607) ◽  
pp. 3242-3253 ◽  
Author(s):  
Roger Cachope
Keyword(s):  
Synaptic Transmission ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Subsequent Development ◽  
Cellular Level ◽  
Cb1 Receptors ◽  
Cannabinoid Receptor 1 ◽  
Signalling System ◽  
Retrograde Signalling ◽  
Amount Of Knowledge

Endocannabinoids (eCBs) act as modulators of synaptic transmission through activation of a number of receptors, including, but not limited to, cannabinoid receptor 1 (CB1). eCBs share CB1 receptors as a common target with Δ 9 -tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Although THC has been used for recreational and medicinal purposes for thousands of years, little was known about its effects at the cellular level or on neuronal circuits. Identification of CB1 receptors and the subsequent development of its specific ligands has therefore enhanced our ability to study and bring together a substantial amount of knowledge regarding how marijuana and eCBs modify interneuronal communication. To date, the eCB system, composed of cannabinoid receptors, ligands and the relevant enzymes, is recognized as the best-described retrograde signalling system in the brain. Its impact on synaptic transmission is widespread and more diverse than initially thought. The aim of this review is to succinctly present the most common forms of eCB-mediated modulation of synaptic transmission, while also illustrating the multiplicity of effects resulting from specializations of this signalling system at the circuital level.

scholarly journals Potential Mechanisms Underlying the Deleterious Effects of Synthetic Cannabinoids Found in Spice/K2 Products

2019 ◽  
Vol 9 (1) ◽  
pp. 14 ◽  
Author(s):  
Balapal Basavarajappa ◽  
Shivakumar Subbanna
Keyword(s):  
Plant Material ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Receptor Type ◽  
Surface Receptors ◽  
Cellular Origin ◽  
The Brain

The chief psychoactive constituent of many bioactive phytocannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC) found in hemp, cannabis or marijuana plants are scientifically denoted by the Latin term, Cannabis sativa, acts on cell surface receptors. These receptors are ubiquitously expressed. To date, two cannabinoid receptors have been cloned and characterized. Cannabinoid receptor type 1 (CB1R) is found to serve as the archetype for cannabinoid action in the brain. They have attracted wide interest as the mediator of all psychoactive properties of exogenous and endogenous cannabinoids and they are abundantly expressed on most inhibitory and excitatory neurons. Recent evidence established that cannabinoid receptor type 2 (CB2R) is also expressed in the neurons at both presynaptic and postsynaptic terminals and are involved in neuropsychiatric effects. Distinct types of cells in many regions in the brain express CB2Rs and the cellular origin of CB2Rs that induce specific behavioral effects are emerging. To mimic the bliss effects of marijuana, synthetic cannabinoids (SCBs) have been sprayed onto plant material, and this plant material has been consequently packaged and sold under brand name “Spice” or “K2”. These SCBs have been shown to maintain their affinity and functional activity for CB1R and CB2R and have been shown to cause severe harmful effects when compared to the effects of Δ9-THC. The present review discusses the potential brain mechanisms that are involved in the deleterious effects of SCBs.

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