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Review
. 2020 Dec 10;63(23):14216-14227.
doi: 10.1021/acs.jmedchem.0c00926. Epub 2020 Sep 23.

Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?

Paula Morales  1 , Ana Lago-Fernandez  1 , Dow P Hurst  2 , Noori Sotudeh  2 , Eugen Brailoiu  3 , Patricia H Reggio  2 , Mary E Abood  3 , Nadine Jagerovic  1
Affiliations
Review

Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?

Paula Morales et al. J Med Chem. .

Abstract

GPR18 is a G-protein-coupled receptor that belongs to the orphan class A family. Even though it shares low sequence homology with the cannabinoid receptors CB1R and CB2R, a growing body of research suggests its relationship with the endocannabinoid system, not only because it is able to recognize cannabinoid ligands but also because of its expression and ability to heteromerize with CBRs. In this review, we aim to analyze the biological relevance, reported modulators, and structural features of GPR18. In order to guide future drug design in this field, highlights from molecular modeling of GPR18 will be provided.

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Figures

Figure 1.
Figure 1.
Chemical structures of lipid-like compounds.
Figure 2.
Figure 2.
Chemical structures of cannabinoid-related compounds.
Figure 3.
Figure 3.
Chemical structure of the natural products amauromine and 27-O-methylasporyzin.
Figure 4.
Figure 4.
Venn diagram classification of compounds tested at GPR18 regarding their activity at the related GPCRs CB1R, CB2R, GPR55 and GPR18. Compounds S4, S5 and S9 have not been included in the diagram since their activity at these other receptors has been reported yet.
Figure 5.
Figure 5.
Chemical structures of selected synthetic GPR18 ligands.,,
Figure 6.
Figure 6.
Human sequence alignments of GPR18, DOR, GPR55, CB1R and CB2R. (A) Transmembrane helix 1 (TMH1), (B) TMH2, (C) TMH3, (D) TMH4, (E) EC2 loop, (F) TMH5, (G) TMH6, and (H) TMH7. Color code: red: prolines; yellow: highly conserved residues across Class A GPCRs; magenta: cysteines in an internal disulfide bridge; blue: cysteines in TMH3 to EC2 disulfide bridge; lavender: GW motif.
Figure 7.
Figure 7.
GPR18 inactive state model. A) Lipid view of the bundle. B) Zoomed in view of the toggle switch residues M7.42 and F6.48. C) Zoomed in view of the “ionic lock” formed by R3.50 and S6.33. This figure has been done for this perspective using our previously reported model.
Figure 8.
Figure 8.
GPR18 binding pocket (EC view, loops have been removed for clarity). Potential interacting residues are displayed in green tubes.
See this image and copyright information in PMC

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