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

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21207693 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20235874 ◽

2019 ◽

Vol 20 (23) ◽

pp. 5874 ◽

Cited By ~ 7

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.

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Cannabinoid receptor type 2 ligands: an analysis of granted patents since 2010

Pharmaceutical Patent Analyst ◽

10.4155/ppa-2021-0002 ◽

2021 ◽

Author(s):

Benjamin Brennecke ◽

Thais Gazzi ◽

Kenneth Atz ◽

Jürgen Fingerle ◽

Pascal Kuner ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Receptor Type ◽

Protective Effects ◽

Cannabinoid Receptor Type 2 ◽

Preclinical Animal Models ◽

G Protein Coupled

The G-protein-coupled cannabinoid receptor type 2 (CB2R) is a key element of the endocannabinoid (EC) system. EC/CB2R signaling has significant therapeutic potential in major pathologies affecting humans such as allergies, neurodegenerative disorders, inflammation or ocular diseases. CB2R agonism exerts anti-inflammatory and tissue protective effects in preclinical animal models of cardiovascular, gastrointestinal, liver, kidney, lung and neurodegenerative disorders. Existing ligands can be subdivided into endocannabinoids, cannabinoid-like and synthetic CB2R ligands that possess various degrees of potency on and selectivity against the cannabinoid receptor type 1. This review is an account of granted CB2R ligand patents from 2010 up to the present, which were surveyed using Derwent Innovation®.

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In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

Scientific Reports ◽

10.1038/s41598-020-77175-y ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Ayat Zagzoog ◽

Kawthar A. Mohamed ◽

Hye Ji J. Kim ◽

Eunhyun D. Kim ◽

Connor S. Frank ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Cannabis Sativa ◽

Cannabinoid Receptor ◽

Partial Agonist ◽

Chinese Hamster ◽

Cannabidiolic Acid

AbstractThe Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.

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Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22158051 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8051

Author(s):

Rodrigo Teodoro ◽

Daniel Gündel ◽

Winnie Deuther-Conrad ◽

Lea Ueberham ◽

Magali Toussaint ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Biological Evaluation ◽

Emission Tomography ◽

Tailored Therapy ◽

Positron Emission ◽

Cannabinoid Receptor Type 2 ◽

Attractive Therapeutic Target ◽

The Brain

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

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Cannabinoids in health and disease: pharmacological potential in metabolic syndrome and neuroinflammation

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2018-0013 ◽

2018 ◽

Vol 36 (2) ◽

Cited By ~ 15

Author(s):

Andrea Mastinu ◽

Marika Premoli ◽

Giulia Ferrari-Toninelli ◽

Simone Tambaro ◽

Giuseppina Maccarinelli ◽

...

Keyword(s):

Cannabis Sativa ◽

Cannabinoid Receptor ◽

Receptor Type ◽

History Of ◽

Health And Disease ◽

Pharmacological Potential ◽

The Brain ◽

Synthesis And Degradation

Abstract The use of different natural and/or synthetic preparations of Cannabis sativa is associated with therapeutic strategies for many diseases. Indeed, thanks to the widespread diffusion of the cannabinoidergic system in the brain and in the peripheral districts, its stimulation, or inhibition, regulates many pathophysiological phenomena. In particular, central activation of the cannabinoidergic system modulates the limbic and mesolimbic response which leads to food craving. Moreover, cannabinoid agonists are able to reduce inflammatory response. In this review a brief history of cannabinoids and the protagonists of the endocannabinoidergic system, i.e. synthesis and degradation enzymes and main receptors, will be described. Furthermore, the pharmacological effects of cannabinoids will be outlined. An overview of the involvement of the endocannabinoidergic system in neuroinflammatory and metabolic pathologies will be made. Finally, particular attention will also be given to the new pharmacological entities acting on the two main receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), with particular focus on the neuroinflammatory and metabolic mechanisms involved.

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Computer modeling of Cannabinoid receptor type 1

ITM Web of Conferences ◽

10.1051/itmconf/20181602008 ◽

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.

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GPR55: a new promising target for metabolism?

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0253 ◽

2017 ◽

Vol 58 (3) ◽

pp. R191-R202 ◽

Cited By ~ 20

Author(s):

Eva Tudurí ◽

Monica Imbernon ◽

Rene Javier Hernández-Bautista ◽

Marta Tojo ◽

Johan Fernø ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Preclinical Models ◽

Endogenous Ligand ◽

Peripheral Tissues ◽

Promising Target ◽

Nutrient Partitioning ◽

G Protein Coupled ◽

Biological Actions

GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.

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