Summary of probe development efforts to identify antagonists of the G-protein coupled receptor 7 (GPR7).
Name: Summary of probe development efforts to identify antagonists of the G-protein coupled receptor 7 (GPR7). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Olivier Civelli, University of California, Irvine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number 1-R03-DA026557-01
Grant Proposal PI: Olivier Civelli
External Assay ID: GPR7_ANT_PRE-HTS_SUMMARY
Name: Summary of probe development efforts to identify antagonists of the G-protein coupled receptor 7 (GPR7).
Heterotrimeric G-protein coupled receptors (GPCRs) are major targets for disease therapeutics, due in part to their broad tissue distribution, structural diversity, varied modes of action, and disease-associated mutations (1-4). For example, targeting of opiod receptors by opiates such as morphine is a widespread clinical application for GPCR modulation in pain management. The recently de-orphanized GPR7 (5) is localized predominantly in the cerebellum and prefrontal cortex (6), with additional expression in the pituitary, hippocampus, amygdala, and spinal cord (7-9). GPR7 is highly conserved in humans and rodents (6), and exhibits structural features of both GPCRs and somatostatin receptors (7). Studies identifying the energy-regulating neuropeptides Neuropeptide W (NPW) and Neuropeptide B (NPB) as endogenous ligands of GPR7 (5, 10), and the development of hyperphagia and obesity in male GPR7 knockout mice (11, 12), implicate GPR7 in feeding behavior. Additional studies identifying GPR7 expression in peripheral Schwann cells (13) and increased GPR7 expression in rat models and human patients with inflammation-associated neuropathic pain (11, 13), suggest a role for GPR7 in mediating the inflammatory pain response. The identification of modulators of GPR7 will provide useful tools to elucidate the diverse roles of this receptor in central neuropeptide signaling and nociception in general.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of GPR7 antagonists. Following uHTS primary and confirmation screening and counterscreening against melanin-concentrating hormone receptor 1 (MCHR1), a hit-to-lead research program was performed by exploring the structure-activity-relationships (SAR) of the identified hit compound. Compound SID 96021160, with an attractive potency/selectivity profile with low nanomolar activity and CC50 > 20 uM against HT29 cells, was selected as a probe.
All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID. A probe report has been submitted. The results of our probe development efforts can be found at http://mlpcn.florida.scripps.edu/index.php/probes/probe-reports. A probe report for SID 96021160 can be found in the Molecular Libraries Bookshelf (PubMed Books) (http://www.ncbi.nlm.nih.gov/books) under ML181.
1. Pan, H.L., Wu, Z.Z., Zhou, H.Y., Chen, S.R., Zhang, H.M., and Li, D.P., Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther, 2008. 117(1): p. 141-61.
2. Lagerstrom, M.C. and Schioth, H.B., Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov, 2008. 7(4): p. 339-57.
3. Thompson, M.D., Cole, D.E., and Jose, P.A., Pharmacogenomics of G protein-coupled receptor signaling: insights from health and disease. Methods Mol Biol, 2008. 448: p. 77-107.
4. Bosier, B. and Hermans, E., Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance. Trends Pharmacol Sci, 2007. 28(8): p. 438-46.
5. Tanaka, H., Yoshida, T., Miyamoto, N., Motoike, T., Kurosu, H., Shibata, K., Yamanaka, A., Williams, S.C., Richardson, J.A., Tsujino, N., Garry, M.G., Lerner, M.R., King, D.S., O'Dowd, B.F., Sakurai, T., and Yanagisawa, M., Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8. Proc Natl Acad Sci U S A, 2003. 100(10): p. 6251-6.
6. O'Dowd, B.F., Scheideler, M.A., Nguyen, T., Cheng, R., Rasmussen, J.S., Marchese, A., Zastawny, R., Heng, H.H., Tsui, L.C., Shi, X., and et al., The cloning and chromosomal mapping of two novel human opioid-somatostatin-like receptor genes, GPR7 and GPR8, expressed in discrete areas of the brain. Genomics, 1995. 28(1): p. 84-91.
7. Brezillon, S., Lannoy, V., Franssen, J.D., Le Poul, E., Dupriez, V., Lucchetti, J., Detheux, M., and Parmentier, M., Identification of natural ligands for the orphan G protein-coupled receptors GPR7 and GPR8. J Biol Chem, 2003. 278(2): p. 776-83.
8. Singh, G., Maguire, J.J., Kuc, R.E., Fidock, M., and Davenport, A.P., Identification and cellular localisation of NPW1 (GPR7) receptors for the novel neuropeptide W-23 by [125I]-NPW radioligand binding and immunocytochemistry. Brain Res, 2004. 1017(1-2): p. 222-6.
9. Lee, D.K., Nguyen, T., Porter, C.A., Cheng, R., George, S.R., and O'Dowd, B.F., Two related G protein-coupled receptors: the distribution of GPR7 in rat brain and the absence of GPR8 in rodents. Brain Res Mol Brain Res, 1999. 71(1): p. 96-103.
10. Fujii, R., Yoshida, H., Fukusumi, S., Habata, Y., Hosoya, M., Kawamata, Y., Yano, T., Hinuma, S., Kitada, C., Asami, T., Mori, M., Fujisawa, Y., and Fujino, M., Identification of a neuropeptide modified with bromine as an endogenous ligand for GPR7. J Biol Chem, 2002. 277(37): p. 34010-6.
11. Kelly, M.A., Beuckmann, C.T., Williams, S.C., Sinton, C.M., Motoike, T., Richardson, J.A., Hammer, R.E., Garry, M.G., and Yanagisawa, M., Neuropeptide B-deficient mice demonstrate hyperalgesia in response to inflammatory pain. Proc Natl Acad Sci U S A, 2005. 102(28): p. 9942-7.
12. Ishii, M., Fei, H., and Friedman, J.M., Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity. Proc Natl Acad Sci U S A, 2003. 100(18): p. 10540-5.
13. Zaratin, P.F., Quattrini, A., Previtali, S.C., Comi, G., Hervieu, G., and Scheideler, M.A., Schwann cell overexpression of the GPR7 receptor in inflammatory and painful neuropathies. Mol Cell Neurosci, 2005. 28(1): p. 55-63.
Summary AID, GPR7, NPBWR1, G-protein coupled receptor 7, pain, feeding, HTS, high throughput screen, primary, 1536, antagonist, antagonism, inhibitor, inhibition, fluorescence, calcium, Fluo-8, fluorescence, dye, Scripps, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
§ Panel component ID.
Details of protocols, compound structures, and results from the original assays can be found in PubChem. Please see AID 1861 for all protocols performed in this probe development effort.
Categorized Comment - additional comments and annotations
Assay Cell Type: HT-29
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML181
PubChem Substance ID (SID) for probe 1: 96021160
PubChem Compound ID (CID) for probe 1: 46172919
Probe type for probe 1: Antagonist
IC50/EC50 (nM) for probe 1: 272
Target for probe 1: GPR7 (gi: 119607128)
Disease relevance for probe 1: Chronic Pain
Anti-target for probe 1: MCH1
Fold selectivity for probe 1: 14
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK98923/ (ID: 2961710)
Grant number for probe 1: DA026557-01
MLP Probe ML# for probe 2: ML250
PubChem Substance ID (SID) for probe 2: 110923218
PubChem Compound ID (CID) for probe 2: 50904505
Probe type for probe 2: Antagonist
IC50/EC50 (nM) for probe 2: <244
Target for probe 2: GPR7 (gi: 119607128)
Disease relevance for probe 2: Chronic Pain
Anti-target for probe 2: MCH1
Fold selectivity for probe 2: >82
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK143551/ (ID: 3036418)
Grant number for probe 2: DA026557-01
NCBI Book chapter title for probe 1: Optimization and Characterization of an Antagonist for G-Protein Coupled Receptor 7 (GPR7)
NCBI Book chapter title for probe 2: Optimization and Characterization of a Second Antagonist for G-protein Coupled Receptor 7 (GPR7)
* Activity Concentration. § Panel component ID.