scholarly journals Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

2015 ◽  
Vol 2015 ◽  
pp. 1-26 ◽  
Author(s):  
Charu Sharma ◽  
Bassem Sadek ◽  
Sameer N. Goyal ◽  
Satyesh Sinha ◽  
Mohammad Amjad Kamal ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Adverse Effects ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Metabolizing Enzymes ◽  
Drug Discovery And Development ◽  
Synthetic Drugs ◽  
Psychiatric Adverse Effects ◽  
G Protein Coupled

The cannabinoid molecules are derived fromCannabis sativaplant which acts on the cannabinoid receptors types 1 and 2 (CB1and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2receptors. However, these synthetic basedCannabisderived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other thanCannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

scholarly journals The neurobiology and evolution of cannabinoid signalling

2001 ◽  
Vol 356 (1407) ◽  
pp. 381-408 ◽  
Author(s):  
Maurice R. Elphick ◽  
Michaelà Egertova
Keyword(s):  
G Protein ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Specific Binding ◽  
Acid Amide ◽  
Presynaptic Terminals ◽  
Smooth Muscle Contractility ◽  
Signalling System ◽  
G Protein Coupled ◽  
The Brain

The plant Cannabis sativa has been used by humans for thousands of years because of its psychoactivity. The major psychoactive ingredient of cannabis is δ 9 –tetrahydrocannabinol, which exerts effects in the brain by binding to a G–protein–coupled receptor known as the CB 1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may occur in the brain, which act as physiological ligands for CB 1 . Two putative endocannabinoid ligands, arachidonylethanolamide (‘anandamide’) and 2–arachidonylglycerol, have been identified, giving rise to the concept of a cannabinoid signalling system. Little is known about how or where these compounds are synthesized in the brain and how this relates to CB 1 expression. However, detailed neuroanatomical and electrophysiological analysis of mammalian nervous systems has revealed that the CB 1 receptor is targeted to the presynaptic terminals of neurons where it acts to inhibit release of ‘classical’ neurotransmitters. Moreover, an enzyme that inactivates endocannabinoids, fatty acid amide hydrolase, appears to be preferentially targeted to the somatodendritic compartment of neurons that are postsynaptic to CB 1 –expressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by postsynaptic cells and acts as a retrograde messenger molecule to modulate neurotransmitter release from presynaptic terminals. Using this model as a framework, we discuss the role of cannabinoid signalling in different regions of the nervous system in relation to the characteristic physiological actions of cannabinoids in mammals, which include effects on movement, memory, pain and smooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non–mammalian animals. Here we review the evidence for the existence of cannabinoid receptors in non–mammalian vertebrates and invertebrates and discuss the evolution of the cannabinoid signalling system. Genes encoding orthologues of the mammalian CB 1 receptor have been identified in a fish, an amphibian and a bird, indicating that CB 1 receptors may occur throughout the vertebrates. Pharmacological actions of cannabinoids and specific binding sites for cannabinoids have been reported in several invertebrate species, but the molecular basis for these effects is not known. Importantly, however, the genomes of the protostomian invertebrates Drosophila melanogaster and Caenorhabditis elegans do not contain CB 1 orthologues, indicating that CB 1 –like cannabinoid receptors may have evolved after the divergence of deuterostomes (e.g. vertebrates and echinoderms) and protostomes. Phylogenetic analysis of the relationship of vertebrate CB 1 receptors with other G–protein–coupled receptors reveals that the paralogues that appear to share the most recent common evolutionary origin with CB 1 are lysophospholipid receptors, melanocortin receptors and adenosine receptors. Interestingly, as with CB 1 , each of these receptor types does not appear to have Drosophila orthologues , indicating that this group of receptors may not occur in protostomian invertebrates. We conclude that the cannabinoid signalling system may be quite restricted in its phylogenetic distribution, probably occurring only in the deuterostomian clade of the animal kingdom and possibly only in vertebrates.

scholarly journals CB1 Cannabinoid Receptor Signaling and Biased Signaling

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5413
Author(s):  
Luciana M. Leo ◽  
Mary E. Abood
Keyword(s):  
Adverse Effects ◽  
G Protein ◽  
Conformational Changes ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Cb1 Cannabinoid Receptor ◽  
Biased Signaling ◽  
G Protein Coupled

The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.

scholarly journals Chemistry, Pharmacology and Therapeutic Potential of Swertiamarin – A Promising Natural Lead for New Drug Discovery and Development

2021 ◽  
Vol Volume 15 ◽  
pp. 2721-2746
Author(s):  
Nur Sakinah Muhamad Fadzil ◽  
Mahendran Sekar ◽  
Siew Hua Gan ◽  
Srinivasa Reddy Bonam ◽  
Yuan Seng Wu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Therapeutic Potential ◽  
Drug Discovery And Development ◽  
New Drug

The Role of Cannabinoids in Schizophrenia: Where Have we Been and Where are we Going?

2017 ◽  
Vol 41 (S1) ◽  
pp. S277-S277
Author(s):  
J. Reis ◽  
G. Pereira
Keyword(s):  
Cannabinoid Receptors ◽  
Psychotic Disorders ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Age At Onset ◽  
Synthetic Cannabinoids ◽  
The Other ◽  
Other Hand ◽  
Increased Risk

IntroductionSeveral studies have shown that both endocannabinoid system (ECS) and synthetic cannabinoids (SC) might be involved in schizophrenia.ObjectivesTo review recent literature on the role of cannabinoids in schizophrenia. The review includes the evidence of cannabis use as a risk factor for the development of schizophrenia, but also the preliminary evidence for the use of cannabinoid-based compounds in the treatment of psychosis.MethodsThe authors made an online search on PubMed for clinical trials and reviews published in the last 12 months, using the keywords: “cannabinoids”, “endocannabinoids”, “phytocannabinoids” and “schizophrenia”.ResultsThe use of Cannabis sativa is associated with increased risk of developing psychotic disorders, including schizophrenia, and earlier age at onset of psychosis. Δ9-Tetrahydrocannabinol (THC) has multiple actions in the brain development, including impairment of neuroplasticity, dysregulation of dopamine and glutamate signaling, and, possibly, neurotoxicity. The ECS has been implicated in psychosis both related and unrelated to cannabis exposure. Cannabinoid receptors type 1 (CB1 R) and type 2 (CB2 R), as well as the endogenous ligand N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) levels, are most likely to be involved in the pathophysiology of this disorder. On the other hand, the antipsychotic effects of some cannabinoids have been investigated in recent studies. Cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV) may have therapeutic potential for the treatment of psychosis.ConclusionsEmerging evidence suggests an important role of ECB system and SC on schizophrenia. On the other hand, recent studies have shown some phytocannabinoids might represent therapeutic promises in this disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Potential metabolic and behavioural roles of the putative endocannabinoid receptors GPR18, GPR55 and GPR119 in feeding

2019 ◽  
Vol 17 (10) ◽  
pp. 947-960 ◽  
Author(s):  
Ricardo E. Ramírez-Orozco ◽  
Ricardo García-Ruiz ◽  
Paula Morales ◽  
Carlos M. Villalón ◽  
J. Rafael Villafán-Bernal ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Eating Behaviour ◽  
Endocannabinoid System ◽  
G Protein Coupled Receptors ◽  
Know How ◽  
Feeding Control ◽  
G Protein Coupled

: Endocannabinoids are ancient biomolecules involved in several cellular (e.g., metabolism) and physiological (e.g., eating behaviour) functions. Indeed, eating behaviour alterations in marijuana users have led to investigate the orexigenic/anorexigenic effects of cannabinoids in animal/ human models. This increasing body of research suggests that the endocannabinoid system plays an important role in feeding control. Accordingly, within the endocannabinoid system, cannabinoid receptors, enzymes and genes represent potential therapeutic targets for dealing with multiple metabolic and behavioural dysfunctions (e.g., obesity, anorexia, etc.). Paradoxically, our understanding on the endocannabinoid system as a cellular mediator is yet limited. For example: (i) only two cannabinoid receptors have been classified, but they are not enough to explain the pharmacological profile of several experimental effects induced by cannabinoids; and (ii) several orphan G protein-coupled receptors (GPCRs) interact with cannabinoids and we do not know how to classify them (e.g., GPR18, GPR55 and GPR119; amongst others). : On this basis, the present review attempts to summarize the lines of evidence supporting the potential role of GPR18, GPR55 and GPR119 in metabolism and feeding control that may explain some of the divergent effects and puzzling data related to cannabinoid research. Moreover, their therapeutic potential in feeding behaviour alterations will be considered.

scholarly journals Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Felipe Patricio ◽  
Alan Axel Morales-Andrade ◽  
Aleidy Patricio-Martínez ◽  
Ilhuicamina Daniel Limón
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Subcortical Structures ◽  
6 Hydroxydopamine

The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson’s disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.

scholarly journals Antioxidative and Anti-Inflammatory Properties of Cannabidiol

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 21 ◽  
Author(s):  
Sinemyiz Atalay ◽  
Iwona Jarocka-Karpowicz ◽  
Elzbieta Skrzydlewska
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Biological Effects ◽  
Antioxidant Properties ◽  
Endocannabinoid System ◽  
Anti Inflammatory ◽  
Pharmacologically Active ◽  
Preclinical And Clinical Studies ◽  
Synthetic Derivatives

Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.

scholarly journals FARMAKOLOGIJA KANABINOIDOV

2015 ◽  
Vol 84 (6) ◽  
Author(s):  
Ilonka Ferjan ◽  
Mojca Kržan ◽  
Metoda Lipnik-Štangelj ◽  
Lovro Žiberna ◽  
Lovro Stanovnik ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Adverse Effects ◽  
Cannabinoid Receptors ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Drug Candidate ◽  
Isolation And Identification ◽  
Increased Risk

The discovery of cannabinoid receptors and endocannabinoid system has led to the potential therapeutic use of cannabis derivatives. Cannabinoids acting through the CB1 receptors modulate the release of other neurotransmitters in central nervous system, whereas the activation of peripheral CB2 receptors results in decreased inflammatory response and increased apoptosis of some tumor cells populations. The cannabinoids have been authorized for chemotherapy-induced nausea and vomiting; stimulation of appetite; to alleviate neuropathic pain and spasticity in multiple sclerosis, and to reduce pain in cancer patients. Efficacy in other diseases and clinical conditions should be proven in ongoing or future clinical trials. Isolation and identification of different cannabinoids from cannabis and synthesis of novel, more selective, derivatives widens their therapeutic potential. However, there are numerous adverse effects reported, especially when cannabinoids formulations with unknown quantitative and qualitative composition are used. Addiction, tolerance, withdrawal symptoms, increased risk of acute myocardial re-infarction, and increased risk of psychosis or worsening of psychosis are the most common adverse effects of cannabinoids. Acute adverse effects e. g. severe central nervous system depression, are more pronounced in children than in adults. Potential cannabinoid medicines should be subject to the same regulations as other potential drugs. Safety and efficacy of any potential drug candidate, regardless whether it is plant-derived or synthesized, should be proven in non-clinical studies and clinical trials, as well as the marketing authorization must be issued by the appropriate drug authority. Patients deserve a quality manufactured product, which always contains the specified amount of "Remedium cardinale."

Use of Genetically Engineered Mice in Drug Discovery and Development: Wielding Occam's Razor to Prune the Product Portfolio

2002 ◽  
Vol 21 (1) ◽  
pp. 55-64 ◽  
Author(s):  
Brad Bolon ◽  
Elizabeth Galbreath
Keyword(s):  
Drug Discovery ◽  
Molecular Mechanisms ◽  
Expressed Sequence Tag ◽  
Therapeutic Potential ◽  
Genetically Engineered ◽  
Drug Discovery And Development ◽  
Occam’S Razor ◽  
Genetically Engineered Mice ◽  
Therapeutic Molecules ◽  
Occam's Razor

Genetically engineered mice (GEMs) that either overexpress (transgenic) or lack (gene-targeted, or “knock-out”) genes are used increasingly in industry to investigate molecular mechanisms of disease, to evaluate innovative therapeutic targets, and to screen agents for efficacy and/or toxicity. High throughput GEM construction in drug discovery and development (DDD) serves two main purposes: to test whether a given gene participates in a disease condition, or to determine the function(s) of a protein that is encoded by an expressed sequence tag (EST, an mRNA fragment for a previously uncharacterized protein). In some instances, pheno-types induced by such novel GEMs also may yield clues regarding potential target organs and toxic effects of potential therapeutic molecules. The battery of tests used in phenotypic analysis of GEMs varies between companies, but the goal is to define one or more easily measured endpoints that can be used to monitor the disease course—especially during in vivo treatment with novel drug candidates. In many DDD projects, overt phenotypes are subtle or absent even in GEMs in which high-level expression or total ablation of an engineered gene can be confirmed. This outcome presents a major quandary for biotechnology and pharmaceutical firms: given the significant expense and labor required to generate GEMs, what should be done with “negative” constructs? The 14th century philosophic al principle known as Occam's razor—that the simplest explanation for a phenomenon is likely the truth—provides a reasonable basis for pruning potential therapeutic molecules and targets. In the context of DDD, Occam's razor may be construed to mean that correctly engineered GEMs lacking obvious functional or structural phenotypes have none because the affected gene is not uniquely essential to normal homeostasis or disease progression. Thus, a “negative” GEM construct suggests that the gene under investigation encodes a ligand or target molecule without significant therapeutic potential. This interpretation indicates that, at least in a market-driven industrial setting, such “negative” projects should be pruned aggressively so that resources may be redirected to more promising DDD ventures.

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