Endocannabinoid System and Endocannabinoid
Discovered in the early 1990s, the endocannabinoid system, named after the plant Cannabis sativa, has emerged as an important and widespread physiological system that is involved in establishing and maintaining human health. In humans, the endocannabinoid system is mainly comprised of endocannabinoids, cannabinoid receptors, and related enzymes, all of which are widely distributed throughout the body and directly involved in a variety of biological activities to maintain homeostasis. In the central nervous system (CNS), the endocannabinoid system plays significant roles in synaptic plasticity, CNS development, physiological, and cognitive process regulations.
In the endocannabinoid system, endocannabinoids, also known as endogenous cannabinoids, are endogenous lipids transmitters that function by binding and activating cannabinoid receptors. The first discovered endocannabinoid was arachidonoyl ethanolamide (also named anandamide) that was identified in the porcine brain. Currently, anandamide and 2-arachidonoylglycerol (2-AG) are the most widely studied and best-characterized endocannabinoids.
Endocannabinoid Biosynthesis and Inactivation
Endocannabinoids are membrane-derived local neuromodulators that are synthesized and inactivated by multiple pathways on demand. As a member of the N-acylethanolamine (NAE) family, anandamide is synthesized by the catalysis of two enzymes, Ca2+-dependent trans-acylase and N-acyl-phosphatidylethanolamineselective phospholipase D, using the N-acylphosphatidylethanolamines as general precursors. 2-AG is produced in a stimulus-dependent or Ca2+-dependent manner via a lysophosphatidylinositol intermediate or a diacylglycerol intermediate.
After released from cells, the endocannabinoids will be rapidly inactivated by uptake into cells and enzymatic hydrolysis. Once reuptake into cells by carrier-mediated mechanisms, anandamide is hydrolyzed through the membrane-bound enzymes fatty acid amide hydrolase into arachidonic acid, or oxidized into PGH2-ethanolamide by cyclooxygenase 2. 2-AG is also hydrolyzed by other enzymes or cyclooxygenase 2-mediated oxidation or non-enzymatic conversion.
Endocannabinoid Inactivation Inhibitors
Since the first description in the 1990s, the endocannabinoid system has already been an attractive therapeutic target for the development of novel drugs. Over these decades, numbers of endocannabinoid system regulators have been developed and described, among which endocannabinoid inactivation inhibitors are those compounds inhibiting the hydrolysis or inactivation of endocannabinoid and serving as potent functional cannabinoid receptor agonists for the treatment of psychiatric disorders. Inhibitors are generally divided into two groups based on the function mechanisms, one is those inhibiting the transportation or cell absorption, the other is those inhibiting the hydrolysis or hydrolases activity. Currently, multiple endocannabinoid inactivation inhibitors have been reported, such as
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N-(4-hydroxyphenyl)-arachidonylamide (AM404): inhibits the transportation and reuptake of endocannabinoids
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Carbamate derivative URB597 and α-ketoheterocycle derivative OL-135: potently inactivate fatty acid amide hydrolases
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OMDM169 and carbamate-based derivative JZL184: selectively inhibit 2-AG hydrolysis
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