Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Nature

Volumn 527, Issue 7579, 2015, Pages 477-483

  Huang, Xi Ping ^a   Karpiak, Joel ^b   Kroeze, Wesley K ^a   Zhu, Hu ^a,f   Chen, Xin ^a,c,d   Moy, Sheryl S ^a   Saddoris, Kara A ^a,g   Nikolova, Viktoriya D ^a   Farrell, Martilias S ^a   Wang, Sheng ^a   Mangano, Thomas J ^a   Deshpande, Deepak A ^e   Jiang, Alice ^a,h   Penn, Raymond B ^e   Jin, Jian ^c,d,i   Koller, Beverly H ^a   Kenakin, Terry ^a   Shoichet, Brian K ^b   Roth, Bryan L ^a,d  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF NORTH CAROLINA   (United States)

^d University of North Carolina   (United States)

^e THOMAS JEFFERSON UNIVERSITY   (United States)

^f NATIONAL INSTITUTES OF HEALTH   (United States)

^g UNIVERSITY OF COLORADO   (United States)

^h Touro College of Osteopathic Medicine   (United States)

ⁱ MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 65; G PROTEIN COUPLED RECEPTOR 68; LORAZEPAM; UNCLASSIFIED DRUG; ANXIOLYTIC AGENT; BENZYL ALCOHOL DERIVATIVE; GPR65 PROTEIN, HUMAN; GPR68 PROTEIN, HUMAN; LIGAND; OGERIN; TRIAZINE DERIVATIVE;

BIOASSAY; GENE EXPRESSION; GENOME; HOMOLOGY; LIGAND; PROTEIN; YEAST;

ALLOSTERISM; ARTICLE; BINDING SITE; CALCIUM MOBILIZATION; CALCIUM TRANSPORT; CONCENTRATION RESPONSE; HYDROGEN BOND; LIGAND BINDING; NONHUMAN; PRIORITY JOURNAL; SCREENING TEST; AGONISTS; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; CONDITIONED REFLEX; DEFICIENCY; DRUG DEVELOPMENT; DRUG EFFECTS; FEAR; FEMALE; HEK293 CELL LINE; HUMAN; KNOCKOUT MOUSE; MALE; MEMORY; METABOLISM; MOUSE; SIGNAL TRANSDUCTION;

MUS;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; ANIMALS; ANTI-ANXIETY AGENTS; BENZYL ALCOHOLS; CONDITIONING, CLASSICAL; DRUG DISCOVERY; FEAR; FEMALE; HEK293 CELLS; HUMANS; LIGANDS; LORAZEPAM; MALE; MEMORY; MICE; MICE, KNOCKOUT; MODELS, MOLECULAR; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; TRIAZINES;

EID: 84948440927     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature15699     Document Type: Article

References (59)

1. Roth, B. L. & Kroeze, W. K. Integrated approaches for genome-wide interrogation of the druggable non-olfactory G protein-coupled receptor superfamily. J. Biol. Chem. 290, 19471-19477 (2015).
2. Davenport, A. P. et al. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65, 967-986 (2013).
3. Chung, S., Funakoshi, T. & Civelli, O. Orphan GPCR research. Br. J. Pharmacol. 153 (suppl. 1), S339-S346 (2008).
4. Knapp, S. et al. A public-private partnership to unlock the untargeted kinome. Nature Chem. Biol. 9, 3-6 (2013).
5. Ferguson, F. M. et al. Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain. J. Med. Chem. 56, 10183-10187 (2013).
6. Leung, D., Hardouin, C., Boger, D. L. & Cravatt, B. F. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nature Biotechnol. 21, 687-691 (2003).
7. Ludwig, M. G. et al. Proton-sensing G-protein-coupled receptors. Nature 425, 93-98 (2003).
8. Mogi, C. et al. Sphingosylphosphorylcholine antagonizes proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1)-mediated inositol phosphate production and cAMP accumulation. J. Pharmacol. Sci. 99, 160-167 (2005).
9. Li, J. et al. Ovarian cancer G protein coupled receptor 1 suppresses cell migration of MCF7 breast cancer cells via a G? 12/13-Rho-Rac1 pathway. J. Mol. Signal. 8, 6 (2013).
10. Singh, L. S. et al. Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer. J. Natl. Cancer Inst. 99, 1313-1327 (2007).
11. Schneider, J. W. et al. Coupling hippocampal neurogenesis to brain pH through proneurogenic small molecules that regulate proton sensing G protein-coupled receptors. ACS Chem. Neurosci. 3, 557-568 (2012).
12. Frick, K. K., Krieger, N. S., Nehrke, K. & Bushinsky, D. A. Metabolic acidosis increases intracellular calcium in bone cells through activation of the proton receptor OGR1. J. Bone Miner. Res. 24, 305-313 (2009).
13. Komarova, S. V., Pereverzev, A., Shum, J. W., Sims, S. M. & Dixon, S. J. Convergent signaling by acidosis and receptor activator of NF-B ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. Proc. Natl Acad. Sci. USA 102, 2643-2648 (2005).
14. Yang, M. et al. Expression of and role for ovarian cancer G-protein-coupled receptor 1 (OGR1) during osteoclastogenesis. J. Biol. Chem. 281, 23598-23605 (2006).
15. Russell, J. L. et al. Regulated expression of pH sensing G protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease. ACS Chem. Biol. 7, 1077-1083 (2012).
16. Mohebbi, N. et al. The proton-activated G protein coupled receptor OGR1 acutely regulates the activity of epithelial proton transport proteins. Cell. Physiol. Biochem. 29, 313-324 (2012).
17. Regard, J. B., Sato, I. T. & Coughlin, S. R. Anatomical profiling of G proteincoupled receptor expression. Cell 135, 561-571 (2008).
18. Chen, Y. J., Huang, C. W., Lin, C. S., Chang, W. H. & Sun, W. H. Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain. Mol. Pain 5, 39 (2009).
19. Saxena, H. et al. The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH. Br. J. Pharmacol. 166, 981-990 (2012).
20. Wang, J., Sun, Y., Tomura, H. & Okajima, F. Ovarian cancer G-protein-coupled receptor 1 induces the expression of the pain mediator prostaglandin E2 in response to an acidic extracellular environment in human osteoblast-like cells. Int. J. Biochem. Cell Biol. 44, 1937-1941 (2012).
21. Li, H. et al. Abnormalities in osteoclastogenesis and decreased tumorigenesis in mice deficient for ovarian cancer G protein-coupled receptor 1. PLoS ONE 4, e5705 (2009).
22. Aoki, H. et al. Proton-sensing ovarian cancer g protein-coupled receptor 1 on dendritic cells is required for airway responses in a murine asthma model. PLoS ONE 8, e79985 (2013).
23. Mogi, C., Nakakura, T. & Okajima, F. Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic-cell functions. Endocr. J. 61, 101-110 (2013).
24. Okajima, F. Regulation of inflammation by extracellular acidification and proton-sensing GPCRs. Cell. Signal. 25, 2263-2271 (2013).
25. Dong, S., Rogan, S. C. & Roth, B. L. Directed molecular evolution of DREADDs: A generic approach to creating next-generation RASSLs. Nature Protocols 5, 561-573 (2010).
26. Mysinger, M. M. & Shoichet, B. K. Rapid context-dependent ligand desolvation in molecular docking. J. Chem. Inf. Model. 50, 1561-1573 (2010).
27. Evers, A. & Klebe, G. Ligand-supported homology modeling of G-proteincoupled receptor sites: models sufficient for successful virtual screening. Angew. Chem. Int. Ed. Engl. 43, 248-251 (2004).
28. Cavasotto, C. N. et al. Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening. J. Med. Chem. 51, 581-588 (2008).
29. Katritch, V., Rueda, M., Lam, P. C.-H., Yeager, M. & Abagyan, R. GPCR 3D homology models for ligand screening: lessons learned from blind predictions of adenosine A2a receptor complex. Proteins 78, 197-211 (2010).
30. Leach, K., Sexton, P. M. & Christopoulos, A. Allosteric GPCR modulators: Taking advantage of permissive receptor pharmacology. Trends Pharmacol. Sci. 28, 382-389 (2007).
31. Keiser, M. J. et al. Relating protein pharmacology by ligand chemistry. Nature Biotechnol. 25, 197-206 (2007).
32. Kalk, P. et al. The adenosine A1 receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure. Br. J. Pharmacol. 151, 1025-1032 (2007).
33. Thompson, S.-A., Wingrove, P. B., Connelly, L., Whiting, P. J. & Wafford, K. A. Tracazolate reveals a novel type of allosteric interaction with recombinant-aminobutyric acidA receptors. Mol. Pharmacol. 61, 861-869 (2002).
34. Tomura, H. et al. Prostaglandin I2 production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cells. J. Biol. Chem. 280, 34458-34464 (2005).
35. Ichimonji, I. et al. Extracellular acidification stimulates IL-6 production and Ca2+ mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 299, L567-L577 (2010).
36. Liu, J. P. et al. Ovarian cancer G protein-coupled receptor 1-dependent and-independent vascular actions to acidic pH in human aortic smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 299, H731-H742 (2010).
37. Matsuzaki, S. et al. Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells. Biochem. Biophys. Res. Commun. 413, 499-503 (2011).
38. Gravius, A., Barberi, C., Schäfer, D., Schmidt, W. J. & Danysz, W. The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats-a comparison. Neuropharmacology 51, 1146-1155 (2006).
39. Daumas, S. et al. Transient activation of the CA3 Kappa opioid system in the dorsal hippocampus modulates complex memory processing in mice. Neurobiol. Learn. Mem. 88, 94-103 (2007).
40. Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274-285 (1992).
41. Onozawa, Y. et al. Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro. Eur. J. Pharmacol. 683, 325-331 (2012).
42. Pompéia, S., Manzano, G. M., Tufik, S. & Bueno, O. F. What makes lorazepam different from other benzodiazepines? J. Physiol. (Lond.) 569, 709 (2005).
43. Greenblatt, D. J. et al. Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam. Clin. Pharmacol. Ther. 20, 329-341 (1976).
44. Schoepp, D. D. Where will new neuroscience therapies come from? Nature Rev. Drug Discov. 10, 715-716 (2011).
45. Eswar, N. et al. Comparative protein structure modeling using MODELLER. Curr. Protoc. Protein Sci. Chapter 2, Unit 2. 9 (2001).
46. Yang, Q. & Sharp, K. A. Building alternate protein structures using the elastic network model. Proteins 74, 682-700 (2009).
47. Jacobson, M. P., Friesner, R. A., Xiang, Z. & Honig, B. On the role of the crystal environment in determining protein side-chain conformations. J. Mol. Biol. 320, 597-608 (2002).
48. Li, J., Zhu, T., Cramer, C. J. & Truhlar, D. G. New class IV charge model for extracting accurate partial charges from wave functions. J. Phys. Chem. A 102, 1820-1831 (1998).
49. Chambers, C. C., Hawkins, G. D., Cramer, C. J. & Truhlar, D. G. Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. J. Phys. Chem. 100, 16385-16398 (1996).
50. Hert, J., Keiser, M. J., Irwin, J. J., Oprea, T. I. & Shoichet, B. K. Quantifying the relationships among drug classes. J. Chem. Inf. Model. 48, 755-765 (2008).
51. Gaulton, A. et al. ChEMBL: A large-scale bioactivity database for drug discovery. Nucleic Acids Res. 40, D1100-D1107 (2012).
52. Mumberg, D., Muller, R. & Funk, M. Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds. Gene 156, 119-122 (1995).
53. Erlenbach, I. et al. Functional expression of M1, M3 and M5 muscarinic acetylcholine receptors in yeast. J. Neurochem. 77, 1327-1337 (2001).
54. Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163-5168 (2007).
55. Christopoulos, A. & Kenakin, T. G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 54, 323-374 (2002).
56. Besnard, J. et al. Automated design of ligands to polypharmacological profiles. Nature 492, 215-220 (2012).
57. Keiser, M. J. et al. Predicting new molecular targets for known drugs. Nature 462, 175-181 (2009).
58. Horvat, S. J. et al. A-kinase anchoring proteins regulate compartmentalized cAMP signaling in airway smooth muscle. FASEB J. 26, 3670-3679 (2012).
59. Huang, X.-P., Mangano, T., Hufeisen, S., Setola, V. & Roth, B. L. Identification of human ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting. Assay Drug Dev. Technol. 8, 727-742 (2010).