Denmark's Novo Nordisk recently acquired Canadian biotech firm Inversago Pharma for up to $1.075 billion. The acquisition is focused on Inversago Pharma's innovative CB1 receptor (CB1R)-based therapy, INV-202. This move makes Novo Nordisk even stronger in the weight loss market by adding to their existing weight loss drug, Wegovy, which works on the GLP-1R. Back to INV-202, it is an oral CB1R antagonist that offers benefits such as appetite reduction, weight loss, and improvements in blood glucose and lipid levels.
Several drugs targeting CNR1 (CBIR/CB1) are showing potential in cancers treatment. For example, Rimonabant is in Phase II clinical trials for the treatment of advanced gastric cancer, while AM251 is undergoing Phase I clinical trials for breast cancer treatment. Thus, CB1R serves as a classical cannabinoid receptor, a target in which more and more pharmaceutical companies are showing keen interest to explore its potential in the treatment of tumors and other metabolic diseases!
1. What is the Endocannabinoid System (ECS)?
5. The Clinical Potential of CNR1 Targeted Therapy
6. CUSABIO CNR1 Recombinant Proteins & Antibodies for Research Use
The endocannabinoid system (ECS) is a vital physiological system that helps maintain the body's balance and regulates lipid metabolism. It consists of endocannabinoids (like AEA and 2-AG), cannabinoid receptors (CNR1 and CNR2), and other receptors (e.g., PPAR, GPR55), along with enzymes like FAAH and MAGL. These components are found throughout the body, including the brain, immune cells, and connective tissues. The ECS plays a key role in various processes, such as neural functions, inflammation, and pain modulation. It also regulates energy metabolism, insulin secretion, blood lipid levels, and sex hormone balance. Recent research has focused on its involvement in energy regulation, autoimmunity, and its potential anti-tumor effects, particularly through the CNR1 receptor [1-2].
Cannabinoid type I receptor (CB1R or CB1, CNR1) is a vital component of the endogenous cannabinoid signaling system, functioning as a G-protein-coupled membrane receptor. The CNR1 gene resides on chromosome 6q14-q15, encoding the CB1R protein with 473 amino acids. It features an extracellular region at the N-terminus (amino acid 117) and an intracellular region at the C-terminus (amino acids 401-473), linked by seven transmembrane segments (Figure 1) [3]. The extracellular region has three hydrophilic domains: e1, e2, and e3. e2 is crucial for cannabinoid binding. CNR1 activation by cannabinoids triggers various intracellular pathways with numerous physiological and pathological functions [4].
CNR1 initially identified to be exclusive to the brain, has been found in various peripheral tissues like the lungs, liver, kidneys, digestive tract, adipose tissue, and skeletal muscle [5-6]. CNR1's activation by cannabinoids triggers complex intracellular signaling pathways within the Endocannabinoid System (ECS), leading to a range of biological effects. These effects include regulating memory, cognition, exercise, mood, AMP levels, substance metabolism, immune function, gene expression, and calcium ions through the calmodulin system. These recent discoveries have renewed interest in CNR1, a classical protein known for over 30 years [7-8]!
Figure 1. CNR1 (CB1) structure [3]
CNR1 (CB1R), a member of the inhibitory G protein-coupled receptor family, has well-documented signaling mechanisms. It primarily modulates intracellular processes by affecting G protein-mediated cyclic AMP production, calcium channels, mitogen-activated protein kinases (MAPKs), and related signaling pathways (Figure 2) [9]. For clarity, let's take the activation of endocannabinoids (EC) as an example.
In the brain, endocannabinoids is served as a retrograde neurotransmitter released by postsynaptic neurons, triggers CB1R-mediated effects. CB1R activation inhibits adenylate cyclase, lowering cAMP levels through the Gi/o protein pathway. It also regulates ion channels, facilitating K+ efflux and decreasing intracellular Ca2+ by inhibiting certain Ca2+ channels. This reduces neurotransmitter release from presynaptic neurons, including GABA and glutamate [9].
CB1R signaling includes phosphorylation and activation of mitogen-activated protein kinases. Phosphorylated CB1R interacts with β-arrestin, regulating G protein-coupled receptor signaling. In specific conditions, CB1R can activate adenylate cyclase via the Gs pathway, increasing intracellular cAMP, and activate Gq-coupled calcium channels selectively. CB1R's pharmacological effects vary in different tissues, possibly due to its ability to form structures with other receptors [9-10].
Figure 2. CNR1 curbs G protein-coupled receptor signaling [9]
The cannabinoid system has a complex anticancer mechanism. When cannabinoids bind to CNR1 (CB1) or CNR2 (CB2) receptors on the cell membrane, they trigger intracellular ceramide synthesis. This activation boosts signaling pathways like ERK, p38MAPK, and PI3K/PKB, leading to apoptosis promotion (Figure 3) [11]. Simultaneously, cannabinoid receptor binding also activates the P27/KIP1, Cyclins, Cdks pathway via ERK and PI3K/PKB, effectively inhibiting cell proliferation [12]. Additionally, cannabinoid binding to CNR1 or CNR2 inhibits AKT/PKB phosphorylation and reduces MMP-2 and MMP-9 secretion, impeding tumor cell migration [13-14].
Figure 3. CNR1 drives the cannabinoid system's anti-tumor mechanism [11]
CNR1 (CB1R) has a complex role in various tumors. It's up-regulated in some, like prostate cancer [15], pancreatic cancer [16], Hodgkin's lymphoma [17], clear cell carcinoma of the kidney [18], and eosinophilic renal cell carcinoma [19]. However, it is down-regulated in poorly-differentiated hepatocellular carcinoma and colorectal cancer [20-21]. Low CNR1 expression in pancreatic cancer is linked to less pain and better prognosis [16]. Conversely, high CNR1 expression in prostate cancer suggests greater malignancy and poorer prognosis [15]. Notably, in hepatocellular carcinoma, high CNR1 expression correlates with a better prognosis [20]. The precise role of CNR1 in different tumors requires further study.
CNR1 may have anticancer effects by influencing tumor growth, angiogenesis, and migration. Most research on its anticancer potential uses cannabinoid agonists. For example, in a mouse model of breast cancer lung metastases, using cannabinoid receptor agonists JWH133 and Win55, 212-2 reduced both the primary tumor and lung metastases [22-23]. Cannabinoids can enhance anti-tumor immunity by influencing the body's immune response, promoting the release of IL-4 and IL-10. However, they can also hinder anti-tumor immunity, potentially contributing to the development of breast cancer [25]. Additionally, in studies involving melanoma and renal cancer, the CNR1-specific inhibitor AM251 substantially inhibited tumor cell proliferation, facilitated apoptosis, and induced G2/M cycle arrest [26-27].
CNR1 (CB1R) overexpression is linked to diseases like obesity, metabolic syndrome, diabetes, and fatty liver [28-32]. Rimonabant, a CNR1-specific antagonist, helps by reducing appetite, liver fat, and body weight through CNR1 control. This treatment improves insulin sensitivity and fat metabolism. Widely used for weight loss, it effectively reduces risk factors for obesity-related diseases [33-34].
The exact mechanism remains unclear, but CB1 receptor inhibitors may enhance insulin sensitivity by curbing genes related to liver fat synthesis, thereby countering obesity in mice [35]. Elevated fatty acid levels disrupt glucose regulation, leading to higher blood sugar levels and impairing pancreatic islet B-cell function. In essence, CB1R activation worsens weight, blood lipids, insulin resistance, and pancreatic function, while CB1R inhibition can reverse these effects, offering potential treatments for glycolipid metabolism-related diseases.
There is also growing interest in the role of CNR1 in affective disorders, depression, intestinal issues, psoriasis, and pain [36-40]. Studies suggest that variations in the CNR1 gene may pose a risk factor for depression, particularly among women and young adults [41]. Additionally, CNR1 plays a pivotal role in regulating gut motility, secretion, sensory functions, and immune responses, which have implications in the development of conditions like irritable bowel syndrome and ulcerative colitis [37].
Moreover, CNR1 and CNR2 expression is elevated in the serum and affected tissue of psoriasis patients, correlating with disease severity [38]. Furthermore, CNR1 agonists demonstrate analgesic effects on neuropathic pain, cancer-related pain, and chronic non-cancer pain, albeit with potential adverse effects like psychiatric disorders, nausea, and drowsiness [39-40].
Two CNR1-based drugs are currently available globally, addressing conditions including obesity and cancer-related pain. As of now, there are over 100 clinical trials focused on CNR1, exploring a variety of fields like endocrinology, neuroscience, and tumor. Researchers are employing CNR1 antagonists, agonists, and modulators to treat conditions such as obesity, diabetes, pain, anxiety, cachexia, drug toxicity, and tumors. As our understanding of CNR1 advances and innovative drugs emerge, CNR1 stands as a significant target in addressing tumors and metabolic disorders.
CNR1, a versatile cannabinoid receptor, plays a role in various physiological functions. It influences mood, appetite, pain, and more, making it a target for drugs addressing conditions like obesity and cancer-related pain. Ongoing clinical research explores CNR1's potential in diverse medical fields, with a focus on antagonists, agonists, and modulators. These investigations on CNR1 bring another strategies for multiple disorders, including obesity, diabetes, and tumors.
To fully support researchers and pharmaceutical companies in their research on CNR1 in tumors and glycolipid metabolism disorders, etc, CUSABIO presents CNR1 active proteins & antibodies to support your research on the mechanism of CNR1 or its potential clinical value.
CUSABIO Cannabinoid receptor 1 (CNR1) protein
● Recombinant Human Cannabinoid receptor 1(CNR1)-VLPs (Active) (Code: CSB-MP005678HU)
The high specifity is detected by Mouse anti-6*His monoclonal antibody.
Immobilized Human CNR1 at 10 μg/ml can bind Anti-CNR1 recombinant antibody (CSB-RA005678MA01HU), the EC50 is 41.72-63.54 ng/mL.
CUSABIO Cannabinoid receptor 1 (CNR1) antibody
CNR1 Recombinant Monoclonal Antibody (Code: CSB-RA005678MA01HU)
References
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