N-Arachidonylglycine

Last updated
N-Arachidonylglycine
N-Arachidonoyl Glycine.svg
Names
IUPAC name
N-[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyl]glycine
Systematic IUPAC name
[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenamido]acetic acid
Other names
N-Arachidonylglycine
Arachidonoyl glycine
NA-glycine
Identifiers
3D model (JSmol)
7652004
ChEBI
ChEMBL
ChemSpider
MeSH Anandamide
PubChem CID
UNII
  • Key: LGEQQWMQCRIYKG-DOFZRALJSA-N Yes check.svgY
  • InChI=1/C22H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)/b7-6-,10-9-,13-12-,16-15-
    Key: YLEARPUNMCCKMP-DOFZRALJSA-N
  • InChI=1S/C22H35NO3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-21(24)23-20-22(25)26/h6-7,9-10,12-13,15-16H,2-5,8,11,14,17-20H2,1H3,(H,23,24)(H,25,26)/b7-6-,10-9-,13-12-,16-15-
  • O=C(NCC(=O)O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
  • O=C(NCC(=O)O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
Properties
C22H35NO3
Molar mass 361.526 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). [1] [2] Since it was first synthesized in 1996, [3] NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. [4] Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. [5] [6] NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. [7] NaGly is found throughout the body and research on its explicit functions is ongoing.

Contents

Biosynthesis and degradation

The biosynthesis and degradation of NaGly is not completely understood. Using biochemical approaches, two proposed pathways include: 1) enzymatic conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoid anandamide. [8] [9] In support of the former "direct" pathway of arachidonic acid and glycine conjugation and hydrolysis, the secreted enzyme PM20D1 and the intracellular amidase FAAH has been identified as enzymatic regulators of NAGly metabolism in mice. [10] [11]

Research

Effects on the nervous system

NAGly has been hypothesized to have a neurophysiological function of pain suppression, supported by evidence that it suppresses formalin-induced pain behavior in rats. [12] In particular, peripherally administered NAGly inhibited phase 2 pain behavior, suggesting either a direct suppression of nociceptive afferents on the nerve or an indirect modulation of the afferents' interstitial environment. [12] In either case, these findings hold promise for NAGly as a means of mitigating postoperative or chronic pain. NAGly is also effective in acute pain models, reducing mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Fruend's complete adjuvant. [13] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly. [14] Other arachidonic acid-amino acid conjugates did not have the same effects and the actions of NaGly were not affected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain. [13] [14]

NaGly was shown to be endogenous ligand for the G-protein couple receptor GPR92 along with farnesyl pyrophosphate. [15] In the dorsal root ganglia (DRG), where GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role of NaGly in the sensory nervous system through the activation of GPR92. [15]

Effects on the immune system

NAGly has been the focus of research on the immune system because of its antinociceptive effects and inhibitory action on components of the immune system. Specifically, it significantly inhibited TNFα and IFNγ production, and it shows potential as a therapeutic treatment for chronic inflammation. [16] Moreover, NAGly has been shown to act as a substrate for cyclooxygenase-2 (COX-2), the enzyme primarily known for producing prostaglandins associated with increases in inflammation and hyperalgesia. In many mammalian tissues that express COX-2, significant levels of NAGly are naturally present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETE-Gly. [17]

Cell migration

NAGly has been hypothesized to induce cell migration in BV-2 microglia cells. [5] The same research suggests that this migration occurs through GPR18. This was verified using GPR18 transfected HEK-293 cells. The same migration wasn't witnessed using non-transfected and GPR55 transfected HEK-293. [5] Additionally, tetrahydrocannabinol and NaGly are full agonists at the GPR18 receptors and induce migration in human endometrial HEC-1B cells. [18] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such as endometriosis.

Cellular respiration

NAGly powerfully stimulates oxygen consumption in multiple cell lines, including murine C2C12 myoblasts and human HEK293T cells. [19] This respiratory bioactivity of NAGly is by increased uncoupled (state4u) mitochondrial respiration and depends on the presence of fatty acid desaturation. [20] NAGly respiration bioactivity can be also abrogated in the presence of serum albumin, which functions as an NAGly carrier in murine blood plasma. [21]

Other targets

Insulin secretion

NaGly was identified as a novel insulin secretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels. [22] Additionally, this action was dependent on extracellular glucose level. [22]

Additional biochemical interactions

NaGly has been shown to inhibit the glycine transporter GLYT2a in a non-competitive fashion with arachidonic acid and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachidonyl amino acids, especially because other conjugated amino acids had similar effects. [23]

Related Research Articles

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

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.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinoid receptor</span> Group of receptors to cannabinoid compounds

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids; phytocannabinoids ; and synthetic cannabinoids. All endocannabinoids and phytocannabinoids are lipophilic.

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Fatty-acid amide hydrolase 1</span>

Fatty-acid amide hydrolase 1 or FAAH-1(EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH. FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.

<span class="mw-page-title-main">2-Arachidonoylglycerol</span> Chemical compound

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).

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. And a receptor being clearly present in bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes, and fatty acid metabolites with affinity for this CB receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA).

<span class="mw-page-title-main">AM404</span> Active metabolite of paracetamol

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.

<span class="mw-page-title-main">NAGly receptor</span> Protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.

<span class="mw-page-title-main">GPR55</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.

<span class="mw-page-title-main">Cannabinoid receptor 2</span> Mammalian protein found in Homo sapiens

The cannabinoid receptor 2(CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids. The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

<span class="mw-page-title-main">GPR119</span> Protein-coding gene in humans

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.

<i>N</i>-Arachidonoyl dopamine Chemical compound

N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

<span class="mw-page-title-main">Oleoylethanolamide</span> Chemical compound

Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor alpha (PPAR-α) agonist. It is a naturally occurring ethanolamide lipid that regulates feeding and body weight in vertebrates ranging from mice to pythons.

<i>N</i>-Acylethanolamine Class of chemical compounds

An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active,. The endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS, a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian, and even further back in time, to the very beginning of bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes. Fatty acid metabolites with affinity for CB receptors are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA), by brown algae which diverged about 1500 MYA, by sponges, which diverged from eumetazoans about 930 MYA, and a lineages that predate the evolution of CB receptors, as CB1 – CB2 duplication event may have occurred prior to the lophotrochozoan-deuterostome divergence 590 MYA. Fatty acid amide hydrolase (FAAH) evolved relatively recently, either after the evolution of fish 400 MYA, or after the appearance of mammals 300 MYA, but after the appearance of vertebrates. Linking FAAH, vanilloid receptors (VR1) and anandamide implies a coupling among the remaining ‘‘older’’ parts of the endocannabinoid system, monoglyceride lipase (MGL), CB receptors, that evolved prior to the metazoan-bilaterian divergence, but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator PEA has been studied in in vitro and in vivo systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, through which it exerts a variety of biological effects, some related to chronic inflammation and pain.

<span class="mw-page-title-main">Abnormal cannabidiol</span> Synthetic, cannabinoid-like compound

Abnormal cannabidiol (Abn-CBD) is a synthetic regioisomer of cannabidiol, which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive effects.

RVD-Hpα (pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).

Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.

<i>N</i>-Acylamides

N-acyl amides are a general class of endogenous fatty acid compounds characterized by a fatty acyl group linked to a primary amine metabolite by an amide bond. Broadly speaking, N-acyl amides fall into several categories: amino acid conjugates, neurotransmitter conjugates, ethanolamine conjugates, and taurine conjugates. N-acyl amides have pleiotropic signaling functions in physiology, including in cardiovascular function, metabolic homeostasis, memory, cognition, pain, motor control and others. Initial attention focused on N-acyl amides present in mammalian organisms, however recently lipid signaling systems consisting of N-acyl amides have also been found to be present in invertebrates, such as Drosophila melanogaster. N-acyl amides play important roles in many biochemical pathways involved in a variety of physiological and pathological processes, as well as the metabolic enzymes, transporters, and receptors that regulate their signaling.

References

  1. ↑ Burstein SH, Huang SM, Petros TJ, Rossetti RG, Walker JM, Zurier RB (October 2002). "Regulation of anandamide tissue levels by N-arachidonylglycine". Biochemical Pharmacology. 64 (7): 1147–50. doi:10.1016/S0006-2952(02)01301-1. PMID   12234618.
  2. ↑ Bradshaw HB, Rimmerman N, Hu SS, Benton VM, Stuart JM, Masuda K, Cravatt BF, O'Dell DK, Walker JM (May 2009). "The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways". BMC Biochemistry. 10: 14. doi:10.1186/1471-2091-10-14. PMC   2689249 . PMID   19460156.
  3. ↑ Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (February 1997). "Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor". Journal of Medicinal Chemistry. 40 (5): 659–67. doi:10.1021/jm960752x. PMID   9057852.
  4. ↑ Bradshaw HB, Rimmerman N, Hu SS, Burstein S, Walker JM (2009). Novel endogenous N-acyl glycines identification and characterization. Vitamins & Hormones. Vol. 81. pp. 191–205. doi:10.1016/S0083-6729(09)81008-X. ISBN   9780123747822. PMID   19647113.
  5. 1 2 3 McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB (March 2010). "N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor". BMC Neuroscience. 11 (1): 44. doi:10.1186/1471-2202-11-44. PMC   2865488 . PMID   20346144.
  6. ↑ Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (September 2006). "Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18". Biochemical and Biophysical Research Communications. 347 (3): 827–32. doi:10.1016/j.bbrc.2006.06.175. PMID   16844083.
  7. ↑ Tegeder I (February 2016). "Endocannabinoids as Guardians of Metastasis". International Journal of Molecular Sciences. 17 (2): 230. doi: 10.3390/ijms17020230 . PMC   4783962 . PMID   26875980.
  8. ↑ Bradshaw HB, Rimmerman N, Hu SS, Benton VM, Stuart JM, Masuda K, Cravatt BF, O'Dell DK, Walker JM (May 2009). "The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways". BMC Biochemistry. 10 (1): 14. doi:10.1186/1471-2091-10-14. PMC   2689249 . PMID   19460156.
  9. ↑ Aneetha H, O'Dell DK, Tan B, Walker JM, Hurley TD (January 2009). "Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals". Bioorganic & Medicinal Chemistry Letters. 19 (1): 237–41. doi:10.1016/j.bmcl.2008.10.087. PMC   2798806 . PMID   19013794.
  10. ↑ Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z, Jedrychowski MP, Lin H, Kamenecka TM, Asara JM, Griffin PR, Banks AS, Nomura DK, Spiegelman BM (July 2018). "Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception". Proc Natl Acad Sci U S A. 115 (29): E6937–45. Bibcode:2018PNAS..115E6937L. doi: 10.1073/pnas.1803389115 . PMC   6055169 . PMID   29967167.
  11. ↑ Kim JT, Terrell SM, Li VL, Wei W, Fischer CR, Long JZ (April 2020). "Cooperative enzymatic control of N-acyl amino acids by PM20D1 and FAAH". eLife. 9: e552115. doi:10.7554/eLife.55211. PMC   7145423 . PMID   32271712.
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  15. 1 2 Oh DY, Yoon JM, Moon MJ, Hwang JI, Choe H, Lee JY, Kim JI, Kim S, Rhim H, O'Dell DK, Walker JM, Na HS, Lee MG, Kwon HB, Kim K, Seong JY (July 2008). "Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92". The Journal of Biological Chemistry. 283 (30): 21054–64. doi: 10.1074/jbc.M708908200 . PMC   2475705 . PMID   18499677.
  16. ↑ WOapplication 9738688,Ferrante A, Poulos A, Pitt M, Easton C, Sleigh M, Rathjen D, Widmer F,"Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids",published 23 October 1997, assigned to Peptide Technology Pty Ltd.and Women's and Children's Hospital Adelaide
  17. ↑ Prusakiewicz JJ, Kingsley PJ, Kozak KR, Marnett LJ (August 2002). "Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2". Biochemical and Biophysical Research Communications. 296 (3): 612–7. doi:10.1016/s0006-291x(02)00915-4. PMID   12176025.
  18. ↑ McHugh D, Page J, Dunn E, Bradshaw HB (April 2012). "Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells". British Journal of Pharmacology. 165 (8): 2414–24. doi:10.1111/j.1476-5381.2011.01497.x. PMC   3423258 . PMID   21595653.
  19. ↑ Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, Nomura DK, Spiegelman BM (June 2016). "The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria". Cell. 166 (2): 424–435. doi:10.1016/j.cell.2016.05.071. PMC   4947008 . PMID   27374330.
  20. ↑ Lin H, Long JZ, Roche AM, Svensson KJ, Dou FY, Chang MR, Strutzenberg T, Ruiz C, Cameron MD, Novick SJ, Berdan CA, Louie SM, Nomura DK, Spiegelman BM, Griffin PR, Kamenecka TM (March 2018). "Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration". J Med Chem. 61 (7): 3224–3230. doi:10.1021/acs.jmedchem.8b00029. PMC   6335027 . PMID   29533650.
  21. ↑ Kim JT, Jedrychowski MP, Wei W, Fernandez D, Fischer CR, Banik SM, Spiegelman BM, Long JZ (May 2020). "A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity". Cell Chem Biol. 27 (9): 1130–1139.e4. doi:10.1016/j.chembiol.2020.04.009. PMC   7502524 . PMID   32402239.
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  23. ↑ Wiles AL, Pearlman RJ, Rosvall M, Aubrey KR, Vandenberg RJ (November 2006). "N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a". Journal of Neurochemistry. 99 (3): 781–6. doi: 10.1111/j.1471-4159.2006.04107.x . PMID   16899062.
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