Cannabinoid receptor 1 (CNR1), also known as CB1 or CBR, is a G protein-coupled receptor (GPCR) for endocannabinoids (eCBs) and has therapeutic potential in diseases such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases.
(Data source: Tian L, et al. Pharmacol Ther. 2025)
Expression distribution of CNR1
CNR1 is mainly expressed in inhibitory neurons, supporting cells, excitatory neurons, smooth muscle cells, and type II alveolar cells.
(Data source: Uniprot)
The structure of CNR1 and its ligands
CNR1 is a 7-transmembrane protein of 472 amino acids belonging to the α-branch of the class A GPCR family. CB1 has a typical class A GPCR structure, consisting of seven transmembrane (7TM) α-helices, three extracellular loops (ECL1-3), three intracellular loops (ICL1-3), and an amphipathic helix 8 (H8). The N-terminus of CB1, specifically residues 99-112 aa , forms a V- shaped loop that inserts into the ligand-binding pocket, acting as a plug and restricting extracellular access. The ECL2 region of CB1 consists of 21 residues and has a complex structure, with four specific residues (268-271 aa ) extending into the binding pocket. These residues are essential for ligand interaction, and two cysteine residues in ECL2 (C257 and C264) are essential for CB1 function. The conformation of ECL2 is stabilized by an intra-loop disulfide bond (C257-C264), a feature also observed in LPA1 and S1P1 receptors. Unlike most class A GPCRs, these lipid receptor structures lack the typical conserved disulfide bond between ECL2 and helix III.
(Data source: Tian L, et al. Pharmacol Ther. 2025)
Signaling pathway and regulation of CNR1
GPCRs, primarily through interactions with heterotrimeric G proteins and inhibitory proteins, coordinate diverse downstream pathways and are crucial for transmitting extracellular signals into the cytoplasm. The G protein complex is composed of three subunits: Gα, Gβ, and Gγ. Gα subunits can be divided into four families: Gαs (stimulatory), Gαi/o (inhibitory), Gαq/11 (activating phospholipase C), and Gα12/13 (regulating cytoskeletal remodeling).
CB1 primarily couples to Gαi/o proteins, inhibiting adenylate cyclase (AC) activity and reducing the accumulation of cyclic adenosine monophosphate (cAMP) in the central nervous system (CNS) and peripheral synapses. Activation of CB1 triggers the phosphorylation and activation of mitogen-activated protein kinases (MAPKs), including ERK1/2, c-Jun N-terminal kinase (JNK), and p38 MAPK.
Phosphorylated CB1 receptors can also recruit β-arrestin 2, which promotes receptor desensitization, internalization, and formation of signaling complexes. β-arrestin 2 primarily terminates G protein signaling and promotes receptor endocytosis, while β-arrestin 1 is essential for activating MAPK signaling cascades and regulating gene expression. Both β-arrestins are involved in ERK1/2 activation, highlighting their complementary roles in CB1 receptor-mediated signaling.
(Data source: Tian L, et al. Pharmacol Ther. 2025)
Targeted therapy for CNR1
Currently, the main treatment method targeting CNR1 is small molecule drugs, and only one monoclonal antibody has entered the clinical research stage.
Nimacimab is a monoclonal antibody targeting CNR1 being developed by Skye Bioscience for the treatment of obesity, diabetic nephropathy, non-alcoholic steatohepatitis, and chronic kidney disease. Skye is conducting a Phase 2 clinical trial (ClinicalTrials.gov: NCT06577090) of nimacimab, a negative allosteric antibody that inhibits CB1 in the peripheral nervous system, for the treatment of obesity. The study is also evaluating the combination of nimacimab and a GLP-1R agonist (Wegovy®). Skye expects to report revenue data from this Phase 2 study in late Q3/early Q4 2025.
