Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18

Schoeder, Clara T.; Kaleta, Maria; Mahardhika, Andhika B.; Olejarz-Maciej, Agnieszka; Łażewska, Dorota; Kieć‐Kononowicz, Katarzyna; Müller, Christa E.

doi:10.1016/j.ejmech.2018.05.050

Cited by 24 publications

(59 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inadvertent upregulation of 15,44 The recent identification of synthetic GPR18 ligands should allow resolution of authentic ligand specificity, as has been the case for other controversial GPCRs. 45,46 We observed evidence of weak activation of yeast expressing CB 2 by…”

Section: Thosementioning

confidence: 92%

N‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132

Foster

Ueno

Chen

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

The G‐protein‐coupled receptor GPR132, also known as G2A, is activated by 9‐hydroxyoctadecadienoic acid (9‐HODE) and other oxidized fatty acids. Other suggested GPR132 agonists including lysophosphatidylcholine (LPC) have not been readily reproduced. Here, we identify N‐acylamides in particular N‐acylglycines, as lipid activators of GPR132 with comparable activity to 9‐HODE. The order‐of‐potency is N‐palmitoylglycine > 9‐HODE ≈ N‐linoleoylglycine > linoleamide > N‐oleoylglycine ≈ N‐stereoylglycine > N‐arachidonoylglycine > N‐docosehexanoylglycine. Physiological concentrations of N‐acylglycines in tissue are sufficient to activate GPR132. N‐linoleoylglycine and 9‐HODE also activate rat and mouse GPR132, despite limited sequence conservation to human. We describe pharmacological tools for GPR132, identified through drug screening. SKF‐95667 is a novel GPR132 agonist. SB‐583831 and SB‐583355 are peptidomimetic molecules containing core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions of N‐acylamides at GPR132. The synthetic cannabinoid CP‐55 940 also activates GPR132. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side‐chain to extend into the membrane bilayer between TM4 and TM5 of GPR132. Small‐molecule ligands are envisaged to occupy a “classical” site encapsulated in the 7TM bundle. Structure‐directed mutagenesis indicates a critical role for arginine at position 203 in transmembrane domain 5 to mediate GPR132 activation by N‐acylamides. Our data suggest distinct modes of binding for small‐molecule and lipid agonists to the GPR132 receptor. Antagonists, such as those described here, will be vital to understand the physiological role of this long‐studied target.

show abstract

Section: Thosementioning

confidence: 92%

N‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132

Foster

Ueno

Chen

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…However, independent confirmation for both lipids is still lacking, as other groups, including ours, have not been able to confirm their activation of GPR18 [25,26]. We recently described the first GPR18 antagonists based on an imidazothiazinone core structure [21,27]. These were discovered by screening a compound library at the human receptor in a β-arrestin recruitment assay using enzyme complementation technology and THC as an agonist.…”

Section: Introductionmentioning

confidence: 91%

“…Synthesis of the compounds which are utilized in this computational study as performed in the Department of Technology and Biotechnology of Drugs Jagiellonian University at Kraków, Poland, and potencies of the compounds were determined at the Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, Germany, as previously reported [21,27]. The synthesis and biological evaluation of the new potent GPR18 antagonist 6 will be published elsewhere.…”

Section: Compoundsmentioning

confidence: 99%

“…In recent years, several studies aimed at the deorphanization of GPR18 have been published. Due to the lack of selective agonists, the moderately potent cannabinoid (CB) receptor agonist ∆ 9tetrahydrocannabinol (THC, 1) has been used in pharmacological studies to activate human GPR18, which led to the suggestion to classify GPR18 as a cannabinoid receptor subtype besides CB1 and CB2 [19][20][21][22]. N-Arachidonoylglycine (NAGly, 2) and resolvin D2 (RvD2, 3) were proposed as endogenous agonists of GPR18 [23,24].…”

Section: Introductionmentioning

confidence: 99%

“…Based on the screening results, a library of imidazothiazinones was synthesized and their structure-activity relationships (SARs) were investigated. PSB-CB-27 (4) and PSB-CB-5 (5; for structures, see Figure 1) were reported as the first potent and selective GPR18 antagonists [21]. In the present study, we constructed a homology model of the human GPR18 to elucidate the binding mode of the only confirmed agonist so far, the natural product THC, and of selected antag- In the present study, we constructed a homology model of the human GPR18 to elucidate the binding mode of the only confirmed agonist so far, the natural product THC, and of selected antagonists by docking and molecular dynamics (MD) simulation studies.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

et al. 2020

Self Cite

View full text Add to dashboard Cite

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

show abstract

Methods for the synthesis of imidazo[2,1-b][1,3]thiazines, their annulated and hydrogenated analogs

Saliyeva,

Slyvka,

Кorotkykh

et al. 2023

Chem Heterocycl Comp

View full text Add to dashboard Cite

Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18

Cited by 24 publications

References 30 publications

N‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132

N‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Methods for the synthesis of imidazo[2,1-b][1,3]thiazines, their annulated and hydrogenated analogs

Contact Info

Product

Resources

About