Related Research Articles
Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.
Monoacylglycerol lipase is an enzyme that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.
Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene FAAH.
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994-1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).
AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.
AMG-3 (part of the AM cannabinoid series) is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC substituted with a dithiolane group on the 3-position side chain. AMG-3 is a potent agonist at both CB1 and CB2 receptors with a Ki of 0.32nM at CB1 and 0.52nM at CB2, and its particularly high binding affinity has led to it being used as a template for further structural development of novel cannabinoid drugs. It has sedative and analgesic effects, with analgesia lasting for up to 36 hours after administration.
A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid, is a non-competitive CB1/CB2 receptor antagonist. And Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.
AM-2201 is a recreational designer drug that acts as a potent but nonselective full agonist for the cannabinoid receptor. It is part of the AM series of cannabinoids discovered by Alexandros Makriyannis at Northeastern University.
AM-1221 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2, with a Ki of 0.28 nM at CB2 and 52.3 nM at the CB1 receptor, giving it around 180 times selectivity for CB2. The 2-methyl and 6-nitro groups on the indole ring both tend to increase CB2 affinity while generally reducing affinity at CB1, explaining the high CB2 selectivity of AM-1221. However, despite this relatively high selectivity for CB2, its CB1 affinity is still too strong to make it useful as a truly selective CB2 agonist, so the related compound AM-1241 is generally preferred for research purposes.
AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a Ki of 1.8 nM at CB1 and 2.2 nM at CB2 as the active (R) enantiomer. It was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131I derivative for mapping the distribution of the CB1 receptor in the brain. AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of JWH-018 but higher than WIN 55,212-2.
AM-1220 is a drug that acts as a potent and moderately selective agonist for the cannabinoid receptor CB1, with around 19 times selectivity for CB1 over the related CB2 receptor. It was originally invented in the early 1990s by a team led by Thomas D'Ambra at Sterling Winthrop, but has subsequently been researched by many others, most notably the team led by Alexandros Makriyannis at the University of Connecticut. The (piperidin-2-yl)methyl side chain of AM-1220 contains a stereocenter, so there are two enantiomers with quite different potency, the (R)-enantiomer having a Ki of 0.27 nM at CB1 while the (S)-enantiomer has a much weaker Ki of 217 nM.
AM-6545 is a drug which acts as a peripherally selective silent antagonist for the CB1 receptor, and was developed for the treatment of obesity. Other cannabinoid antagonists such as rimonabant have been marketed for this application, but have subsequently been withdrawn from sale because of centrally mediated side effects such as depression and nausea. Because AM-6545 does not cross the blood–brain barrier to any significant extent, it does not produce these kinds of side effects, but has still been shown to effectively reduce appetite and food consumption in animal studies.
AM-2389 is a classical cannabinoid derivative which acts as a potent and reasonably selective agonist for the CB1 receptor, with a Ki of 0.16 nM, and 26x selectivity over the related CB2 receptor. It has high potency in animal tests of cannabinoid activity, and a medium duration of action. Replacing the 1',1'-dimethyl substitution of the dimethylheptyl side chain of classical cannabinoids with cyclopropyl or cyclopentyl results in higher potency than cyclobutyl, but only the cyclobutyl derivatives show selectivity for CB1 over CB2. High selectivity for CB1 over CB2 is difficult to achieve (cf. AM-906, AM-1235), as almost all commonly used CB1 agonists have similar or greater affinity for CB2 than CB1, and the only truly highly selective CB1 agonists known as of 2012 are eicosanoid derivatives such as O-1812.
AM-1714 (part of the AM cannabinoid series) is a drug that acts as a reasonably selective agonist of the peripheral cannabinoid receptor CB2, with sub-nanomolar affinity and 490x selectivity over the related CB1 receptor. In animal studies it has both analgesic and anti-allodynia effects. The 9-methoxy derivative AM-1710 has similar CB2 affinity but only 54x selectivity over CB1.
The endocannabinoid transporters (eCBTs) are transport proteins for the endocannabinoids. Most neurotransmitters are water-soluble and require transmembrane proteins to transport them across the cell membrane. The endocannabinoids on the other hand, are non-charged lipids that readily cross lipid membranes. However, since the endocannabinoids are water immiscible, protein transporters have been described that act as carriers to solubilize and transport the endocannabinoids through the aqueous cytoplasm. These include the heat shock proteins (Hsp70s) and fatty acid-binding proteins for anandamide (FABPs). FABPs such as FABP1, FABP3, FABP5, and FABP7 have been shown to bind endocannabinoids. FABP inhibitors attenuate the breakdown of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture. One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds that act as an anti-nociceptive agent with mild anti-inflammatory activity in mice. These truxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice and are active components of a Chinese herbal medicine used to treat rheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their anti-nociceptive effects.
alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.
N-acylethanolamine acid amide hydrolase (NAAA) EC 3.5.1.- is a member of the choloylglycine hydrolase family, a subset of the N-terminal nucleophile hydrolase superfamily. NAAA has a molecular weight of 31 kDa. The activation and inhibition of its catalytic site is of medical interest as a potential treatment for obesity and chronic pain. While it was discovered within the last decade, its structural similarity to the more familiar acid ceramidase (AC) and functional similarity to fatty acid amide hydrolase (FAAH) allow it to be studied extensively.
An endocannabinoid enhancer (eCBE) is a type of cannabinoidergic drug that enhances the activity of the endocannabinoid system by increasing extracellular concentrations of endocannabinoids. Examples of different types of eCBEs include fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, and endocannabinoid transporter (eCBT) inhibitors. An example of an actual eCBE is AM404, the active metabolite of the analgesic paracetamol and a dual FAAH inhibitor and eCBRI.
AM-7438 is a drug which is a cannabinoid receptor agonist, developed by the research team led by Dr Alexandros Makriyannis. It is a derivative of Δ8-THC which has been substituted with a side chain containing a metabolically labile ester group, allowing the molecule to be rapidly metabolised to an inactive form, in a similar manner to drugs such as remifentanil, remimazolam and SN 35210. This means that while AM-7438 retains potent cannabinoid effects, it has a much shorter duration of action than most related compounds.
References
- ↑ "Alexandros Makriyannis". Northeastern University College of Science. Retrieved 2 December 2018.
- ↑ "Pioneer in Chemical Biology". Ellines. Retrieved 3 January 2019.
- 1 2 3 "Alexandros Makriyannis". Advancing Drug Development Forum. 2018-08-06. Archived from the original on 3 January 2019. Retrieved 2 December 2018.
- 1 2 3 4 "Alexandros Makriyannis, Ph.D." American Chemical Society, Division of Medicinal Chemistry. Retrieved 2 December 2018.
- ↑ "Cannabinoid receptor structure revealed". National Institutes of Health (NIH). November 1, 2016.
- ↑ Singer, Thea (October 20, 2016). "Structure of the brain's 'marijuana receptor' revealed". News@Northeastern. Northeastern University.
- ↑ Perrier, Jean (October 19, 2017). "Peut-on fumer de l'herbe sans être stone ?" [Could we smoke weed without getting stoned?]. GQ France (in French).
- ↑ Davi, Christine Regan (August 3, 2018). "Can the opioid crisis be fixed?". News@Northeastern. Northeastern University.
