Selective Inhibitors of Monoacylglycerol Lipase as a Treatment for Neurological Disorders

Background: Acute stress elicits the rapid formation of two endocanabinoid ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA). These endogenous lipids bind to the CB1 cannabinoid receptor and inhibit pain sensation by acting as non-opioid stress-induced analgesics. AEA and 2-AG are metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol (MGL) respectively. Technology: University of California, Irvine researchers have developed a novel class of compounds that selectively inhibit the hydrolysis of 2-AG. When injected directly into the periaqueductal gray matter (PAG) of the midbrain, these compounds elevate endogenous 2-AG levels and enhance the non-opioid component of stress-induced analgesia in a CB1-dependent manner.

These inhibitors were developed under the assumption that similarities should exist between the substrate-binding sites of MGL and FAAH. Both enzymes cleave arachidonic-acid derivatives, suggesting that their binding pockets, though structurally unrelated, may accommodate inhibitors of similar bulk and hydrophobicity. This premise directed synthetic and pharmacological efforts, which eventually resulted in the identification of the first potent and selective inhibitors of intracellular MGL activity.
Application: These agents represent the first class of selective MGL inhibitors and provide therefore new pharmacophoric scaffolds to develop neurotherapeutic agents for stress-related disorders (e.g., depression and anxiety), neurodegenerative disorders (e.g., Alzheimer disease) and neuropathic pain.

Type of Offer: Licensing



« More Pharmaceutical Patents

---