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BioAssay: AID 1880

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
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Probe(2)
 
 
Active(2)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Probe(2)
 
 
Active(2)
 
 
AID: 1880
Data Source: The Scripps Research Institute Molecular Screening Center (GPR7_ANT_PRE-HTS_SUMMARY)
BioAssay Type: Panel, Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-07-21
Modify Date: 2012-03-02

Data Table ( Complete ):           Probe    Active    All
Target
BioActive Compounds: Chemical Probe: 2    Active: 2
Depositor Specified Assays
Show more
AIDNameTypeComment
1861Fluorescence-based primary cell-based high throughput screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7).screeningPrimary screen (GPR7 antagonists in singlicate)
463250Late-stage fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1)confirmatoryDose response counterscreen (MCHR1 antagonists in triplicate)
463251Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7)confirmatoryDose response (GPR7 antagonists in triplicate)
463253Late-stage luminescence-based cell-based dose response assay to identify antagonists of the G-protein coupled receptor 7 (GPR7): Cytotoxicity assayconfirmatoryDose response counterscreen (Cytotoxicity in triplicate)
485339Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7): Intracellular calcium releaseconfirmatoryDose response (GPR7 antagonists in triplicate)
504401Late-stage counterscreen panel assay for GPR7 antagonists: Ricerca HitProfilingScreen + CYP450otherLate-stage counterscreen panel assay (Ricerca hit profiling screen + CYP450)
504868Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7) Set 2confirmatoryLate-stage dose response (GPR7 antagonists in triplicate)
504886Late-stage results from the probe development effort to identify antagonists of the G-protein coupled receptor 7 (GPR7): luminescence-based cell-based dose response counterscreen assay to determine cytotoxicity of antagonist compounds Set 2confirmatoryLate-stage dose response counterscreen (cytotoxicity in six replicates)
504889Late-stage fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) Set 2confirmatoryLate-stage dose response counterscreen (MCHR1 antagonists in triplicate)
540345Late-stage counterscreen panel assay for GPR7 antagonists: Ricerca HitProfilingScreen + CYP450: Set 2otherLate-stage counterscreen panel assay (Ricerca Hit Profiling Screen + CYP450 Set 2)
540365Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7) Set 3confirmatoryLate-stage dose response (GPR7 antagonists in triplicate)
540371Late-stage fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) Set 3confirmatoryLate-stage dose response counterscreen (MCHR1 antagonists in triplicate)
588326Late-stage results from the probe development effort to identify antagonists of the G-protein coupled receptor 7 (GPR7): luminescence-based cell-based dose response counterscreen assay to determine cytotoxicity of antagonist compounds Set 3confirmatoryLate-stage dose response counterscreen (Cytotoxicity of antagonist compounds with 6 replicates)
588562Late-stage fluorescence-based cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7): percent inhibitionotherLate-stage assay (GPR7 antagonists in triplicate)
588563Late-stage fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) Set 5confirmatoryLate-stage dose response counterscreen (MCHR1 antagonists in triplicate)
588564Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7) Set 4confirmatoryLate-stage fluorescence-based dose response (GPR7 antagonists in triplicate)
588566Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7) Set 5confirmatoryLate-stage dose response (GPR7 antagonists in triplicate)
588568Late-stage fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) Set 4confirmatoryLate-stage dose response counterscreen (MCHR1 antagonists in triplicate)
588581Late-stage fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) Set 6confirmatoryLate-stage dose response counterscreen (MCHR1 antagonists in triplicate)
588583Late-stage fluorescence-based dose response cell-based screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7) Set 6confirmatoryLate-stage dose response (GPR7 antagonists in triplicate)
1952Fluorescence-based confirmation cell-based high throughput screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7).screening
2251Fluorescence-based dose response cell-based high throughput screening assay to identify antagonists of the G-protein coupled receptor 7 (GPR7).confirmatory
2257Fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based high throughput dose response assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1).confirmatory
2148Fluorescence-based counterscreen for antagonists of the G-protein coupled receptor 7 (GPR7): cell-based high throughput screening assay to identify antagonists of the melanin-concentrating hormone receptor 1 (MCHR1).screening
Description:
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).

Description:

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.


References:

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.

Keywords:

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 Information
Related BioAssays
    Data Table(Active)    Data Table(All)Show more
PID§NameSubstancePanel TargetsDescriptionAdditional Information
ActiveInactive
1AID 463251neuropeptides B/W receptor 1 [Homo sapiens] [gi:119607128]
Taxonomy id: 9606
Gene id: 2831
2AID 485339neuropeptides B/W receptor 1 [Homo sapiens] [gi:119607128]
Taxonomy id: 9606
Gene id: 2831
3AID 463250melanin-concentrating hormone receptor 1 [Homo sapiens] [gi:88758590]
Taxonomy id: 9606
Gene id: 2847
4AID 540365_1neuropeptides B/W receptor 1 [Homo sapiens] [gi:119607128]
Taxonomy id: 9606
Gene id: 2831
5AID 540365_2neuropeptides B/W receptor 1 [Homo sapiens] [gi:119607128]
Taxonomy id: 9606
Gene id: 2831
6AID 540365_3neuropeptides B/W receptor 1 [Homo sapiens] [gi:119607128]
Taxonomy id: 9606
Gene id: 2831
7AID 540371_1melanin-concentrating hormone receptor 1 [Homo sapiens] [gi:88758590]
Taxonomy id: 9606
Gene id: 2847
8AID 540371_2melanin-concentrating hormone receptor 1 [Homo sapiens] [gi:88758590]
Taxonomy id: 9606
Gene id: 2847
9AID 540371_3melanin-concentrating hormone receptor 1 [Homo sapiens] [gi:88758590]
Taxonomy id: 9606
Gene id: 2847
10AID 588326

§ Panel component ID.
Protocol
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.
Result Definitions
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TIDNameDescriptionPID§Panel TargetsHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML #Unique alphanumeric identifier assigned to a chemical probe molecule within the Molecular Libraries Probe Production Centers Network (MLPCN).String
2IC50 [AID 463251]*Data from AID 463251. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.1neuropeptides B/W receptor 1 [Homo sapiens]FloatμM
3IC50 [AID 485339]*Data from AID 485339. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.2neuropeptides B/W receptor 1 [Homo sapiens]FloatμM
4IC50 [AID 463250]*Data from AID 463250. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.3melanin-concentrating hormone receptor 1 [Homo sapiens]FloatμM
5IC50 [AID 540365_1]*Data from AID 540365_1. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.4neuropeptides B/W receptor 1 [Homo sapiens]FloatμM
6IC50 [AID 540365_2]*Data from AID 540365_2. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.5neuropeptides B/W receptor 1 [Homo sapiens]FloatμM
7IC50 [AID 540365_3]*Data from AID 540365_3. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.6neuropeptides B/W receptor 1 [Homo sapiens]FloatμM
8Qualifier [AID 540371_1]Data from AID AID 540371_1. Activity Qualifier identifies if the resultant data IC50 came from a fitted curve or was determined manually to be less than or greater than its listed IC50 concentration.7melanin-concentrating hormone receptor 1 [Homo sapiens]String
9IC50 [AID 540371_1]*Data from AID 540371_1. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.7FloatμM
10Qualifier [AID 540371_2]Data from AID AID 540371_2. Activity Qualifier identifies if the resultant data IC50 came from a fitted curve or was determined manually to be less than or greater than its listed IC50 concentration.8melanin-concentrating hormone receptor 1 [Homo sapiens]String
11IC50 [AID 540371_2]*Data from AID 540371_2. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.8FloatμM
12Qualifier [AID 540371_3]Data from AID AID 540371_3. Activity Qualifier identifies if the resultant data IC50 came from a fitted curve or was determined manually to be less than or greater than its listed IC50 concentration.9melanin-concentrating hormone receptor 1 [Homo sapiens]String
13IC50 [AID 540371_3]*Data from AID 540371_3. The value for concentration at which 50% inhibition is observed; IC50 shown in uM.9FloatμM
14Qualifier [AID 588326]Data from AID AID 588326. Activity Qualifier identifies if the resultant data CC50 came from a fitted curve or was determined manually to be less than or greater than its listed CC50 concentration.10String
15CC50 [AID 588326]*Data from AID 588326. The value for concentration at which 50% inhibition is observed; CC50 shown in uM.10FloatμM

* Activity Concentration. § Panel component ID.
Additional Information
Grant Number: 1-R03-DA026557-01

Classification
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