Pharmacotherapy of Neurochemical Imbalances
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
The interesting fact observed was that though cannabinoids exist only naturally in plant with no biological connection in humans, many parts of brain, namely cerebral cortex, basal ganglia, cerebellum, and hippocampus express huge numbers of receptors for cannabinoids. This made scientific workers to think of endogenous substances which may be selectively interacting with CB and whose action is facilitated by Delta-9-tetrahydrocannabinol. Thus in 1992, the first endogenous ligand of CB1 receptors later labeled as Anandamide was discovered in porcine brain. The name, Anandamide was derived from the Sanskrit word ‘Ananda’ meaning ‘Bliss.’ With the discovery of anandamide, many other metabolites collectively termed as endocannabinoids, were characterized and discovered to act as useful agonists of CB in the brain, however they were not superior in efficacy than anandamide (Devane et al., 1992). The endocannabinoids are found in the brain or other tissues only in small amounts. Similar to other lipid mediators, they are formed and released locally on call. Anandamide and endocannabinoids are rapidly inactivated by reuptake through transporter and by metabolism through the enzyme fatty acid amide hydrolase. The anandamide is formed from the precursor N-arachidonic phosphatidyl ethanolamine by hydrolysis in presence of an enzyme phosphodiesterase enzyme phospholipase D (Iversen, 2003).
Endocannabinoid System & Cannabinoid Receptors
Betty Wedman-St Louis in Cannabis as Medicine, 2019
Fatty acid amide hydrolase (FAAH) is a main gatekeeper in cardiac functions, substance abuse disorders, and regulation of nociception [11–14]. Cell culture and animal studies have shown inhibiting FAAH may be a treatment option in anxiety disorders [15]. Certain flavonoids have been found to inhibit FAAH in its effort to break down the endocannabinoid anandamide [16]. Anandamide is responsible for maintaining basic endocannabinoid signaling. FAAH inhibition increases endocannabinoid concentrations and decreases pro-inflammatory cytokines while increasing the production of anti-inflammatory cytokines [10].
Endogenous Cannabinoid Receptors and Medical Cannabis
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
The biosynthesis and degradation of enzymes such as fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) that break down endocannabinoids are prime targets for new drug development. Manipulating these enzymes may harness innate processes that counteract disease states, and plant-derived molecules such as cannabidiol (CBD) hold significant promise for this. Allosteric modulators of endocannabinoid receptors other than CBD are a target of future drug development, as their effects on the receptors’ activity can potentially enhance endogenous cannabinoid function.
Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Alessandro Deplano, Mariateresa Cipriano, Federica Moraca, Ettore Novellino, Bruno Catalanotti, Christopher J. Fowler, Valentina Onnis
N-acylethanolamines (NAE) are endogenous lipid ligands that regulate numerous physiological functions in the body due to activation of cannabinoid receptors, peroxisome proliferator-activated receptor-alpha (PPAR-α), and other targets1. Arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide, oleoylethanolamide, stearoylethanolamide and linoleoylethanolamide are the principal N-acylethanolamines. Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme largely responsible for the hydrolytic degradation of N-acylethanolamines. The FAAH catalytic mechanism exploits an unusual catalytic triad, Ser-Ser-Lys, in which the basic Lys142 activates the nucleophilic Ser241, involving the Ser217 as a “proton shuttle”2. Structurally, FAAH is a homodimer enzyme bound to the membrane3 (Figure 1(a)). Its binding cavity is characterised by a series of separate channels that are crucial for its biological function: (i) the membrane access channel (MAC) that connects the membrane-bound region with the enzyme active site; (ii) the acyl-chain binding channel (ACB) including the catalytic triad and residues involved in the substrate binding; (iii) the cytosolic port (CP), which represents a way out for the hydrophilic product of the substrates hydrolysation4 (Figure 1(b)).
Understanding the implications of the biobehavioral basis of nicotine addiction and its impact on the efficacy of treatment
Published in Expert Review of Respiratory Medicine, 2018
Nikki Bozinoff, Bernard Le Foll
Another strategy that has been explored is the modulation of anandamide, an endocannabinoid that binds to CB1 receptors with high affinity and may also have non-cannabinoid-mediated effects. Enhancing anandamide transmission by blocking its degradation using fatty acid amide hydrolase (FAAH) inhibitors is currently being explored. FAAH inhibitors have been shown to reduce acquisition of nicotine intravenous self-administration and nicotine-induced conditioned place preferences [89] and decrease elevation of DA levels induced by nicotine in the NAc in preclinical trials [90]. Similar effects have been observed with two lead anandamide transport inhibitor compounds (AM 404 and VDM 11) that dose dependently attenuated reinstatement of nicotine-seeking behavior induced by nicotine-associated stimuli and by nicotine priming, but without affecting direct nicotine taking behaviors [91]. Unfortunately, a death in a recent clinical trial with the FAAH inhibitor BIA 10-2474 has recently halted further research in this area [92]. However, it has now been established that the negative effects of BIA 10-2474 were not related to FAAH inhibition and instead related to an off-target mechanism [93]. This is further supported by the excellent safety of the different FAAH inhibitors that have been tested in humans. The FDA has now allowed the research to continue on FAAH inhibitors.
Cannabis for cancer – illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology
Published in Expert Opinion on Investigational Drugs, 2019
The EGFR family of extracellular protein ligands includes the receptor tyrosine kinases EGFR, human epidermal growth factor receptor 2 (HER2/Neu), Her 3, Her 4. EGFR is an important transmembrane protein, as mutations in its expression may result in cancer, and inhibition of its signaling pathways prevent tumor spread. Fatty acid amide hydrolase (FAAH), a serine hydrolase that metabolizes N-acylethanolamines like AEA, OEA, and PEA, is known to be overexpressed in certain cancer cells and its inhibition can enhance patient survival. Blockage of FAAH raises the level of AEA, inhibiting the EGFR signaling pathway and leading to cell arrest and apoptosis [61]. Both in vivo and in vitro, activation of CB2 receptors decreased migration and invasion of estrogen positive and negative breast cancer cells by suppressing EGFR and insulin-like growth factor tumorigenic pathways [62].
Related Knowledge Centers
- Anandamide
- Dictyostelium Discoideum
- Enzyme
- In Vivo
- Protease
- Metabolism
- Cannabinoid
- Serine Hydrolase
- N-Acylethanolamine
- Gene