CB1

Synonyms

CNR1, Cannabinoid Receptor 1, CANN6, CB-R, CNR, CB1, Central Cannabinoid Receptor, CB1K5, CB1A, CB1R, Receptor, Cannabinoid, CB1, Cannabinoid Receptor 1 (Brain)

Description

G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta-tetrahydrocannabinol (THC) . Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP . In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission. In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca channels in a constitutive, as well as agonist-dependent manner . In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca channels leads to vasodilation and decreased vascular tone. Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes. In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake. Peripherally modulates energy metabolism. In high carbohydrate diet-induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism. In response to cannabinoid anandamide, elicits a proinflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion. In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells .Binds both 2-AG and anandamide.Only binds 2-AG with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 2 in assays measuring GTP binding to membranes.Only binds 2-AG with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 3 in assays measuring GTP binding to membranes.

KO Status

In Vitro

Drug Information

Launched drugs: 2
Drugs in clinical trials: 11
Latest Research Phase: Approved

Drug Name

Code

Phase

Company

Indications

Clinical Trials

Cannabidiol/Dronabinol

GW-1000, MGC-ODT, PPP-001, GW-1000-02, BOL-DP-o-04

Approved

Gw Pharmaceuticals

Peripheral Nervous System Diseases, Cancer Pain, Chronic Pain, Spasm, Pain, Squamous Cell Carcinoma of Head and Neck, Renal Insufficiency, Diabetic Neuropathies, Neoplasms, Kidney Diseases, Multiple Sclerosis, Neuralgia, Postherpetic, Muscle Spasticity, Acute Pain, Sciatica, Neuralgia, Stress Disorders, Post-Traumatic, Osteoarthritis, Knee, Hepatic Insufficiency, Hidradenitis Suppurativa, Low Back Pain, Cerebral Palsy

Cannabidiol

GWP-42003-P, BOL-DP-o-05, GW-42003, BTX-1204, ZYN-002, PTL-101, CHI-902, APH-1501, AVCN-583601, GLA-015, BTX-1503, BTX-1801, BTX-1702, PBX-1308

Approved

Gw Pharmaceuticals, Insys Therapeutics, Isa Pharmaceuticals

Migraine Disorders, Seizures, Tuberous Sclerosis, Rett Syndrome, Anxiety, Schizophrenia, Diabetes Mellitus, Type 2, Fatty Liver, Autism Spectrum Disorder, Graft vs Host Disease, Musculoskeletal Pain, Diabetic Neuropathies, Chronic Urticaria, Opioid-Related Disorders, Lennox Gastaut Syndrome, Azotemia, Multiple Sclerosis, Phobia, Social, Fragile X Syndrome, Spasms, Infantile, Epilepsy, Absence, Dyslipidemias, Epilepsy, Prader-Willi Syndrome, Fear, Hepatitis, Autoimmune, Substance Withdrawal Syndrome, Colitis, Ulcerative, Drug Resistant Epilepsy, Panic, Epilepsies, Myoclonic, Crohn Disease, Dermatitis, Atopic

AEF-0117

AEF-0117

Phase 2 Clinical

National Institute On Drug Abuse, Aelis Farma

Substance-Related Disorders, Marijuana Abuse

AX-1602

AX-1602

Phase 2 Clinical

Axim Biotech

Psoriasis, Dermatitis, Atopic, Vitiligo

11C-MePPEP

11C-MePPEP

Phase 2 Clinical

Eli Lilly And Company

Substance-Related Disorders, Obesity

Nimacimab

RYI-018, RYI-028, JNJ-2463

Phase 2 Clinical

Bird Rock Bio, Janssen Global Services Llc

Non-alcoholic Fatty Liver Disease, Diabetic Nephropathies, Obesity, Diabetic Gastroparesis

Tetrahydrocannabivarin

THCV, O-4394, GW-42004, GWP-42004, DELTA9-THCV

Phase 2 Clinical

Gw Pharmaceuticals Plc

Diabetes Mellitus, Type 2, Dyslipidemias

Cannabidiol/Tetrahydrocannabivarin (40:1)

Phase 2 Clinical

Gw Pharmaceuticals Plc

Schizophrenia

ART-2713

ART-2713

Phase 1 Clinical

Astra Zeneca Gmbh, Neomed Inc, Pfizer Pharmaceuticals Ltd (China)

Anorexia

ZYN-001

ZYN-001

Phase 1 Clinical

Zynerba Pharmaceuticals

Neuralgia, Fibromyalgia

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