The endocannabinoid system is a set of proteins and endogenous ligands that regulates a variety of biological processes. It consists of cannabinoid receptors 1 (CB1) and 2 (CB2), the natural ligands 2-arachidonyl glycerol (2-AG) and N-arachidonylethanolamide (AEA or Anandamide), as well as proteins responsible for the hydrolysis of these ligands, such as monoacyl glycerol lipase (MAGL), fatty acid amide hydrolase (FAAH) and alpha/beta hydrolase domain 6 (ABHD6). CB1 is located mainly in brain tissues, while CB2 is found in the periphery. Endocannabinoid modulation is a research topic in neuroscience, immunology, cancer and obesity research.
Cannabinoid receptors 1 and 2 are G-protein coupled receptors (GPCRs). The results of activation/inhibition of CB1 and CB2 are still being explored.
CB Mixed Agonists
Besides endogenous ligands 2-AG and AEA, many synthetic endocannabinoids have been discovered. Mixed agonists (which interact with both CB1 and CB2) include WIN 55,212-2 and CP 55,940. Both of these agonist are able stimulate cannabinoid signaling, with no preference between the two receptors. Stimulation of CB1 and CB2 has been tied to analgesia, anti-diabetic, anti-obesity and anti-inflammation.
Selective CB antagonists
Antagonism of the cannabinoid receptors is under study for decreasing CB signaling. CB antagonists have been used in neuroscience, cancer and immunology research. AM251, a selective CB1 inverse agonist demonstrated benefits in an anti-obesity system. AM630, a selective CB2 inverse agonist, activates TRPA1 in sensory neurons.
CB1 Antagonists/Inverse Agonists
CB2 Antagonists/Inverse Agonists
CB2 selective agonists are ubiquitous throughout current academic literature. Synthetic CB2 agonists have been used to study the role of endocannabinoids in neurodegenerative disorders, diabetes, obesity and cancer. Agonists of the CB2 receptor have especially shown benefits as analgesic and anti-allodynic compounds.
Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of AEA to arachidonic acid. Inhibition of FAAH results in an increase in AEA, which can stimulate CB1 and CB2 and activate down stream signaling pathways. FAAH inhibition is under investigation for pain attenuation and the reduction of neuro-inflammation. FAAH inhibitor URB597 demonstrates analgesic effects in mice. Inhibitor PF-3845 also reduces pain in mice stimulated with LPS, and reduces inflammation in mice models for traumatic brain injury.
Monoacylglycerol lipase (MAGL) is responsible for the hydrolysis of 2-AG to arachidonic acid. Increasing the amount of 2-AG stimulates cannabinoid signaling. Inhibition of MAGL increases 2-AG, showing the benefits of increased 2-AG. JZL 184, an inhibitor of MAGL decreases pain in multiple mouse models, showing anti-nociceptive and reducing pain-related to cancer drugs in mice. URB602, another inhibitor of MAGL, also demonstrates anti-nociceptive properties.
Alpha/Beta hydrolase domain 6 (ABHD6) also hydrolyzes 2-AG to arachidonic acid. The ABHD inhibitor WWL70 reduces weight gain in diet-induced obese mice. It also has anti-inflammatory properties by reducing the amount of pro-inflammatory prostaglandin expression.
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