NAGly receptor

{{Short description|Protein-coding gene in the species Homo sapiens}}

N-Arachidonyl glycine receptor (NAGly receptor), also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene.{{cite journal |vauthors=Gantz I, Muraoka A, Yang YK, Samuelson LC, Zimmerman EM, Cook H, Yamada T | title = Cloning and chromosomal localization of a gene (GPR18) encoding a novel seven transmembrane receptor highly expressed in spleen and testis | journal = Genomics | volume = 42 | issue = 3 | pages = 462–6 | date = Sep 1997 | pmid = 9205118 | doi = 10.1006/geno.1997.4752 }}{{cite web |title= Entrez Gene: GPR18 G protein-coupled receptor 18 |url= https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2841 }} 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.{{cite journal |vauthors=Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M | title = Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18 | journal = Biochem. Biophys. Res. Commun. | volume = 347 | issue = 3 | pages = 827–32 | date = September 2006 | pmid = 16844083 | doi = 10.1016/j.bbrc.2006.06.175 }}{{cite journal | author = Burstein S | title = The elmiric acids: biologically active anandamide analogs | journal = Neuropharmacology | volume = 55 | issue = 8 | pages = 1259–64 | date = December 2008 | pmid = 18187165 | pmc = 2621443 | doi = 10.1016/j.neuropharm.2007.11.011 }}{{cite journal |vauthors=Bradshaw HB, Lee SH, McHugh D | journal = Prostaglandins Other Lipid Mediat. | volume = 89 | issue = 3–4 | pages = 131–4 | date = September 2009 | pmid = 19379823 | pmc = 2740803 | doi = 10.1016/j.prostaglandins.2009.04.006 | title = Orphan endogenous lipids and orphan GPCRS: A good match }} It has been found to be involved in the regulation of intraocular pressure.{{cite journal | vauthors = Caldwell MD, Hu SS, Viswanathan S, Bradshaw H, Kelly ME, Straiker A | title = A GPR18-based signalling system regulates IOP in murine eye | journal = British Journal of Pharmacology | volume = 169 | issue = 4 | pages = 834–43 | date = June 2013 | pmid = 23461720 | pmc = 3687663 | doi = 10.1111/bph.12136 }}

Research supports the hypothesis that GPR18 is the abnormal cannabidiol receptor and N-arachidonoyl glycine, the endogenous lipid metabolite of anandamide, initiates directed microglial migration in the CNS through activation of GPR18, though recent evidence demonstrates that NAGly was not shown to be a GPR18 agonist in rat sympathetic neurons.{{cite journal |vauthors=Lu VB, Puhl HL, Ikeda SR | title = N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. | journal = Molecular Pharmacology | volume = 83 | issue = 1 | pages = 267–82 | date = Jan 2013 | pmid = 23104136 | doi=10.1124/mol.112.081182 | pmc=3533477}}

Resolvin D2 (RvD2), a member of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid metabolites, is an activating ligand for GPR18; RvD2 and its activation of GPR18 contribute to the resolution of inflammatory responses as well as inflammation-based and other diseases in animal models and are proposed to do so in humans.{{cite journal | vauthors = Shinohara M, Serhan CN | title = Novel Endogenous Proresolving Molecules:Essential Fatty Acid-Derived and Gaseous Mediators in the Resolution of Inflammation | journal = Journal of Atherosclerosis and Thrombosis | volume = 23 | issue = 6 | pages = 655–64 | year = 2016 | pmid = 27052783 | doi = 10.5551/jat.33928 | pmc = 7399282 | doi-access = free }} Furthermore, RvD2 is a metabolite of the omega-3 fatty acid, docosahexaenoic acid (DHA); the metabolism of DHA to RvD2 and RvD2's activation of GPR18 is proposed to one among many other mechanisms for the anti-inflammatory and other beneficial effects attributed to omega-3 fatty acid-rich diets{{cite journal | vauthors = Calder PC | title = Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 469–84 | year = 2015 | pmid = 25149823 | doi = 10.1016/j.bbalip.2014.08.010 }}

Ligands

;Agonists

Ligands found to bind to GPR18 as agonists include:{{cite journal |vauthors=McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB | title = N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor | journal = BMC Neurosci | volume = 11 | pages = 44 | year = 2010 | pmid = 20346144 | pmc = 2865488 | doi = 10.1186/1471-2202-11-44 | doi-access = free }}{{cite journal |vauthors=McHugh D, Page J, Dunn E, Bradshaw HB | title = Δ(9) -THC and N-arachidonyl glycine are full agonists at GPR18 and cause migration in the human endometrial cell line, HEC-1B | journal = Br J Pharmacol | volume = 165 | issue = 8 | pages = 2414–24 | date = May 2011 | pmid = 21595653 | doi = 10.1111/j.1476-5381.2011.01497.x | pmc = 3423258 }}

N-Arachidonoylglycine (NAGly)
Abnormal cannabidiol (Abn-CBD)
AM-251 - partial agonist
Cannabidiol - partial agonist
CBG-DMH{{cite journal | vauthors = Szczesniak AM, Maor Y, Robertson H, Hung O, Kelly ME | title = Nonpsychotropic cannabinoids, abnormal cannabidiol and canabigerol-dimethyl heptyl, act at novel cannabinoid receptors to reduce intraocular pressure | journal = Journal of Ocular Pharmacology and Therapeutics | volume = 27 | issue = 5 | pages = 427–35 | date = October 2011 | pmid = 21770780 | doi = 10.1089/jop.2011.0041 }}
O-1602
Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) - THC is actually a more potent agonist at GPR18 than at CB₁ or CB₂, with Ki of 0.96nM at GPR18, 8.1nM at GPR55, 25.1nM at CB₁ and 35.2nM at CB₂.{{cite journal | author = Ashton JC | title = The atypical cannabinoid o-1602: Targets, actions, and the central nervous system | journal = Central Nervous System Agents in Medicinal Chemistry | volume = 12 | issue = 3 | pages = 233–239 | year = 2012 | pmid = 22831390 | doi = 10.2174/187152412802430156 }}
Anandamide (N-arachidonoyl ethanolamine, AEA)
Arachidonylcyclopropylamide (ACPA){{cite book | editor =Abood ME | title = endoCANNABINOIDS: actions at non-CB1/CB2 cannabinoid receptors | year = 2012 | publisher = Springer | location = New York | isbn = 978-1-4614-4668-2 |vauthors=McHugh D, Bradshaw HB | chapter = GPR18 and NAGly Signaling: New Members of the Endocannabinoid Family or Distant Cousins? }}
Resolvin D2 (RvD2) {{cite journal |vauthors=Chiang N, Dalli J, Colas RA, Serhan CN | title = Identification of Resolvin D2 Receptor Mediating Resolution of Infections and Organ Protection | journal = J. Exp. Med. | volume = 212 | issue = 8 | pages = 1203–1217 | year = 2015 | pmid = 26195725 | doi = 10.1084/jem.20150225 | pmc=4516788| url = https://dash.harvard.edu/bitstream/handle/1/24983913/4516788.pdf?sequence=1 }}Zheng Z, Zhao M, Xu Y, Zhang J, Peng S, Liu J, Pan W, Yin Z, Wei C, Qin JJ, Wan J, Wang M. Resolvin D2/GPR 18 axis ameliorates pressure overload-induced heart failure by inhibiting pro-inflammatory macrophage polarization. J Lipid Res. 2024 Dec;65(12):100679. {{doi|10.1016/j.jlr.2024.100679}} {{PMID|39490925}}
PSB-KD107
PSB-KK1415

;Antagonists

Amauromine{{cite journal | vauthors = Schoeder CT, Kaleta M, Mahardhika AB, Olejarz-Maciej A, Łażewska D, Kieć-Kononowicz K, Müller CE | title = Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18 | journal = European Journal of Medicinal Chemistry | volume = 155 | pages = 381–397 | date = July 2018 | pmid = 29902723 | doi = 10.1016/j.ejmech.2018.05.050 | s2cid = 49214747 }}
O-1918
PSB-CB5{{cite journal | vauthors = Rempel V, Atzler K, Behrenswerth A, Karcz T, Schoeder C, Hinz S, Kaleta M, Thimm D, Kiec-Kononowicz K, Müller CE | display-authors = 6 | year = 2014 | title = Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55 | journal = Med. Chem. Commun. | volume = 5 | issue = 5| pages = 632–649 | doi = 10.1039/C3MD00394A }}

NAGly receptor

Ligands

References

Further reading