Class A Orphans with only surrogate ligands | G protein-coupled receptors

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Class A Orphans
Class A Orphans with only surrogate ligands

Class A Orphans with only surrogate ligands C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Preliminary pairings with surrogate ligands have been described for these GPCRs. Endogenous ligands have not been identified.

Receptors

GPR21 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id	92
Nomenclature	GPR21
Genes	GPR21 (Hs), Gpr21 (Mm), Gpr21 (Rn)
Ensembl ID	ENSG00000188394 (Hs), ENSMUSG00000053164 (Mm), ENSRNOG00000042269 (Rn)
UniProtKB AC	Q99679 (Hs), Q8BX79 (Mm)
Principal transduction	G_q/G₁₁ family
Comment	Positive benefit in models of diabetes/obesity [7,16] were not observed in another study [26]. A cryo-EM structure of unliganded GPR21 bound to G proteins has been reported [12]. GRA2 is reported as an inverse agonist [2].

GPR27 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

Nomenclature

GPR27

Previous and unofficial names

SREB1 | super conserved receptor expressed in brain 1

Genes

GPR27 (Hs), Gpr27 (Mm), Gpr27 (Rn)

Ensembl ID

ENSG00000170837 (Hs), ENSMUSG00000072875 (Mm), ENSRNOG00000010880 (Rn)

UniProtKB AC

Q9NS67 (Hs), O54897 (Mm), Q9JJH3 (Rn)

Principal transduction

G_q/G₁₁ family

Agonists

compound 5128535 [17]

PT-91 [17]

compound 1a [PMID: 27184081] (Inverse agonist) [27]

Comment

A complex mix of plasmalogens evoked phosphorylation of ERK and PKB in mouse cultured hippocampal neurones that could be inhibited with shRNA directed against GPR27 [8]. Compound 5128535 [4-5,17] and PT-91 [17] function as surrogate agonists, while compound 1a is reported as an inverse agonist [27]. Knockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose-stimulated insulin secretion [10].

GPR52 C Show summary »« Hide summary More detailed page go icon to follow link

GPR85 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id	121
Nomenclature	GPR85
Previous and unofficial names	Srep2 \| SREB2 \| SREB \| Super conserved receptor expressed in brain 2 \| PKrCx1
Genes	GPR85 (Hs), Gpr85 (Mm), Gpr85 (Rn)
Ensembl ID	ENSG00000164604 (Hs), ENSMUSG00000048216 (Mm), ENSRNOG00000024636 (Rn)
UniProtKB AC	P60893 (Hs), P60894 (Mm), P60895 (Rn)
Principal transduction	-
Comment	Compound 1a [PMID: 27184081] [27] and compound 3i [22] are reported as inverse agonists. Proposed to regulate hippocampal neurogenesis in the adult, as well as neurogenesis-dependent learning and memory [3].

GPR88 C Show summary »« Hide summary More detailed page go icon to follow link

References

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1. Bi Y, Dzierba CD, Fink C, Garcia Y, Green M, Han J, Kwon S, Kumi G, Liang Z, Liu Y et al.. (2015) The discovery of potent agonists for GPR88, an orphan GPCR, for the potential treatment of CNS disorders. Bioorg Med Chem Lett, 25 (7): 1443-7. [PMID:25754495]

2. Bordano V, Kinsella GK, Cannito S, Dianzani C, Gigliotti CL, Stephens JC, Monge C, Bocca C, Rosa AC, Miglio G et al.. (2022) G protein-coupled receptor 21 in macrophages: An in vitro study. Eur J Pharmacol, 926: 175018. [PMID:35537492]

3. Chen Q, Kogan JH, Gross AK, Zhou Y, Walton NM, Shin R, Heusner CL, Miyake S, Tajinda K, Tamura K et al.. (2012) SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory. Eur J Neurosci, 36 (5): 2597-608. [PMID:22697179]

4. Dolanc D, Zorec TM, Smole Z, Maver A, Horvat A, Pillaiyar T, Trkov Bobnar S, Vardjan N, Kreft M, Chowdhury HH et al.. (2022) The Activation of GPR27 Increases Cytosolic L-Lactate in 3T3 Embryonic Cells and Astrocytes. Cells, 11 (6). [PMID:35326460]

5. Dupuis N, Laschet C, Franssen D, Szpakowska M, Gilissen J, Geubelle P, Soni A, Parent AS, Pirotte B, Chevigné A et al.. (2017) Activation of the Orphan G Protein-Coupled Receptor GPR27 by Surrogate Ligands Promotes β-Arrestin 2 Recruitment. Mol Pharmacol, 91 (6): 595-608. [PMID:28314853]

6. Fer M, Amalric C, Arban R, Baron L, Ben Hamida S, Breh-Schlanser P, Cui Y, Darcq E, Eickmeier C, Faye V et al.. (2024) Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies. J Med Chem, 67 (13): 11296-11325. [PMID:38949964]

7. Gardner J, Wu S, Ling L, Danao J, Li Y, Yeh WC, Tian H, Baribault H. (2012) G-protein-coupled receptor GPR21 knockout mice display improved glucose tolerance and increased insulin response. Biochem Biophys Res Commun, 418 (1): 1-5. [PMID:22155242]

8. Hossain MS, Mineno K, Katafuchi T. (2016) Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling. PLoS One, 11 (3): e0150846. [PMID:26934370]

9. Jin C, Decker AM, Makhijani VH, Besheer J, Darcq E, Kieffer BL, Maitra R. (2018) Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake. J Med Chem, 61 (15): 6748-6758. [PMID:30011199]

10. Ku GM, Pappalardo Z, Luo CC, German MS, McManus MT. (2012) An siRNA screen in pancreatic beta cells reveals a role for Gpr27 in insulin production. PLoS Genet, 8 (1): e1002449. [PMID:22253604]

11. Li JX, Thorn DA, Jin C. (2013) The GPR88 receptor agonist 2-PCCA does not alter the behavioral effects of methamphetamine in rats. Eur J Pharmacol, 698 (1-3): 272-7. [PMID:23123351]

12. Lin X, Chen B, Wu Y, Han Y, Qi A, Wang J, Yang Z, Wei X, Zhao T, Wu L et al.. (2023) Cryo-EM structures of orphan GPR21 signaling complexes. Nat Commun, 14 (1): 216. [PMID:36639690]

13. Logue SF, Grauer SM, Paulsen J, Graf R, Taylor N, Sung MA, Zhang L, Hughes Z, Pulito VL, Liu F, Rosenzweig-Lipson S, Brandon NJ, Marquis KL, Bates B, Pausch M. (2009) The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders?. Mol Cell Neurosci, 42 (4): 438-47. [PMID:19796684]

14. Nakahata T, Tokumaru K, Ito Y, Ishii N, Setoh M, Shimizu Y, Harasawa T, Aoyama K, Hamada T, Kori M et al.. (2018) Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel series of G protein-coupled receptor 52 (GPR52) agonists. Bioorg Med Chem, 26 (8): 1598-1608. [PMID:29478803]

15. Nishiyama K, Suzuki H, Harasawa T, Suzuki N, Kurimoto E, Kawai T, Maruyama M, Komatsu H, Sakuma K, Shimizu Y et al.. (2017) FTBMT, a Novel and Selective GPR52 Agonist, Demonstrates Antipsychotic-Like and Procognitive Effects in Rodents, Revealing a Potential Therapeutic Agent for Schizophrenia. J Pharmacol Exp Ther, 363 (2): 253-264. [PMID:28851764]

16. Osborn O, Oh da Y, McNelis J, Sanchez-Alavez M, Talukdar S, Lu M, Li P, Thiede L, Morinaga H, Kim JJ et al.. (2012) G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice. J Clin Invest, 122 (7): 2444-53. [PMID:22653059]

17. Pillaiyar T, Wozniak M, Abboud D, Rasch A, Liebing AD, Poso A, Kronenberger T, Stäubert C, Laufer SA, Hanson J. (2023) Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency. J Med Chem, 66 (24): 17118-17137. [PMID:38060818]

18. Poulter S, Austin N, Armstrong R, Barnes M, Bucknell SJ, Higueruelo A, Banerjee J, Mead A, Mould R, MacSweeney C et al.. (2023) The Identification of GPR52 Agonist HTL0041178, a Potential Therapy for Schizophrenia and Related Psychiatric Disorders. ACS Med Chem Lett, 14 (4): 499-505. [PMID:37077397]

19. Power ME, Fernandez NR, Oni OP, Kalia A, Rourke JL. (2024) The non-nutritive sweetener sucralose increases β-arrestin signaling at the constitutively active orphan G protein-coupled receptor GPR52. Can J Physiol Pharmacol, 102 (2): 116-127. [PMID:37748201]

20. Rahman MT, Decker AM, Ben Hamida S, Perrey DA, Chaminda Lakmal HH, Maitra R, Darcq E, Kieffer BL, Jin C. (2023) Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation. J Med Chem, 66 (4): 2964-2978. [PMID:36749855]

21. Russell B, Barrus MM, Tremblay M, Ma L, Hrelja K, Wong C, Hynes TJ, Hobson S, Grottick AJ, Winstanley CA. (2021) GPR52 agonists attenuate ropinirole-induced preference for uncertain outcomes. Behav Neurosci, 135 (1): 8-23. [PMID:33119328]

22. Sakai A, Yasui T, Watanave M, Tatsumi R, Yamamoto Y, Takano W, Tani Y, Okamura I, Hirai H, Takeda S. (2022) Development of novel potent ligands for GPR85, an orphan G protein-coupled receptor expressed in the brain. Genes Cells, 27 (5): 345-355. [PMID:35194900]

23. Setoh M, Ishii N, Kono M, Miyanohana Y, Shiraishi E, Harasawa T, Ota H, Odani T, Kanzaki N, Aoyama K et al.. (2014) Discovery of the first potent and orally available agonist of the orphan G-protein-coupled receptor 52. J Med Chem, 57 (12): 5226-37. [PMID:24884590]

24. Stott LA, Brighton CA, Brown J, Mould R, Bennett KA, Newman R, Currinn H, Autore F, Higueruelo AP, Tehan BG et al.. (2021) Characterisation of inverse agonism of the orphan-G protein-coupled receptor GPR52 by cannabinoid ligands Cannabidiol and O-1918. Heliyon, 7 (6): e07201. [PMID:34189291]

25. Wang C, Zhang YF, Guo S, Zhao Q, Zeng Y, Xie Z, Xie X, Lu B, Hu Y. (2021) GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes. J Med Chem, 64 (2): 941-957. [PMID:33185430]

26. Wang J, Pan Z, Baribault H, Chui D, Gundel C, Véniant M. (2016) GPR21 KO mice demonstrate no resistance to high fat diet induced obesity or improved glucose tolerance. F1000Res, 5: 136. [PMID:27081476]

27. Yanai T, Kurosawa A, Nikaido Y, Nakajima N, Saito T, Osada H, Konno A, Hirai H, Takeda S. (2016) Identification and molecular docking studies for novel inverse agonists of SREB, super conserved receptor expressed in brain. Genes Cells, 21 (7): 717-27. [PMID:27184081]

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.