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BioAssay: AID 652075

Late-stage results from the probe development effort to identify antagonists of OPRK1: radiometric-based biochemical hERG counterscreen assay

Name: Late-stage results from the probe development effort to identify antagonists of OPRK1: radiometric-based biochemical hERG counterscreen assay. ..more
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 Tested Compounds
 Tested Compounds
All(1)
 
 
Inactive(1)
 
 
 Tested Substances
 Tested Substances
All(1)
 
 
Inactive(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 652075
Data Source: The Scripps Research Institute Molecular Screening Center (HERG_INH_RAD_2X%INH)
Depositor Category: NIH Molecular Libraries Probe Production Network, Assay Provider
BioAssay Version:
Deposit Date: 2013-03-05
Hold-until Date: 2013-10-21
Modify Date: 2013-10-21

Data Table ( Complete ):           View All Data
Target
Tested Compound:
Related Experiments
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AIDNameTypeComment
652031Maybridge screen to identify antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based assayScreeningdepositor-specified cross reference: Maybridge screen (OPRK1 inhibitors in singlicate)
652032Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response assayConfirmatorydepositor-specified cross reference: Late-stage dose response (OPRK1 antagonists in quadruplicate)
652033Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response OPRD1 counterscreenConfirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRD1 antagonists in quadruplicate)
652034Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response OPRM1 counterscreenConfirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRM1 antagonists in quadruplicate)
652045Summary of the probe development efforts to identify antagonists of the kappa 1 (OPRK1) opioid receptorSummarydepositor-specified cross reference: Summary (OPRK1 antagonists)
652108Late-stage results from the probe development effort to identify antagonists of OPRK1: In vivo tail flick assayOtherdepositor-specified cross reference
652076Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based biochemical cytochrome P450 inhibition assayOthersame project related to Summary assay
652077Late-stage fluorescence-based cell-based dose response assay for antagonists of kappa opioid receptor 1 (OPRK1)Confirmatorysame project related to Summary assay
652078Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based pharmacokinetic plasma protein binding assayOthersame project related to Summary assay
652079Late-stage counterscreen for antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based dose response assay to identify antagonists of Sphingosine 1-Phosphate Receptor 1 (S1P1)Confirmatorysame project related to Summary assay
652080Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response OPRD1 counterscreen, Set 2Confirmatorysame project related to Summary assay
652081Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response OPRM1 counterscreen, Set 2Confirmatorysame project related to Summary assay
652082Fluorescence-based cell-based confirmation assay for antagonists of kappa opioid receptor 1 (OPRK1)Othersame project related to Summary assay
652083Late-stage results from the probe development effort to identify antagonists of OPRK1: CEREP radiometric-based biochemical counterscreen panel assayOthersame project related to Summary assay
652084Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response assay, Set 2.Confirmatorysame project related to Summary assay
652085Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based in vivo plasma and brain levelsOthersame project related to Summary assay
652086Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response counterscreen assay to determine cytotoxicity of test compoundsConfirmatorysame project related to Summary assay
652087Counterscreen for antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based assay to identify antagonists of Sphingosine 1-Phosphate Receptor 1 (S1P1)Othersame project related to Summary assay
652088Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based biochemical hepatic microsome stability assayOthersame project related to Summary assay
652113Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based parallel artificial membrane permeability (PAMPA) assayOthersame project related to Summary assay
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Lakshmi A. Devi, Mount Sinai School of Medicine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: R03NS053751
Grant Proposal PI: Lakshmi A. Devi, Mount Sinai School of Medicine
External Assay ID: HERG_INH_RAD_2X%INH

Name: Late-stage results from the probe development effort to identify antagonists of OPRK1: radiometric-based biochemical hERG counterscreen assay.

Description:

Potent and selective OPRK antagonists will be useful for studying the mechanisms involved in OPRK-mediated analgesia and may have therapeutic value as novel analgesics with an improved side effect profile to currently available drugs. Studies have identified a role for dynorphin and OPRK stimulation in neuropathic pain (1). The dynorphins act as endogenous agonists at the opioid receptors, including OPRK (2), and the increased dynorphin expression in neuropathic pain also leads to a sustained activation of OPRK (1, 3). The mechanisms and neural circuits in OPRK-mediated analgesia are active areas of study; it is hoped those studies will assist in the development of novel analgesics that bypass OPRK-mediated depression (4-5). A role for dynorphin/OPRK in modulating drug addiction has been proposed (for review, see (6-7)). The function of dynorphin/OPRK systems in addiction appears to be diverse, and may modulate drug-seeking behavior depending on factors such as drug history, pattern of intake, and stress (for review, see (6)). The availability of potent and selective OPRK ligands may help unravel these mechanisms, as well as prove to be of therapeutic utility. Evidence from preclinical studies indicates that the dynorphin/OPRK system may be dysregulated in affective psychiatric disorders (for review, see (6, 8)). However, solid evidence from clinical studies is lacking. There is increasing evidence for a potential involvement of dynorphin/OPRK in schizophrenia; OPRK agonists appear to induce symptoms in humans and animals that are present in schizophrenia (8-10). Thus, the availability of new research tools such as potent and selective OPRK antagonists will facilitate understanding the physiological and pathophysiological mechanisms of dynorphin/OPRK systems and their roles in psychiatric disease in humans.

References:

1. Xu, M., et al., Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci, 2004. 24(19): p. 4576-84.
2. Chavkin, C., I.F. James, and A. Goldstein, Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science, 1982. 215(4531): p. 413-5.
3. Xu, M., et al., Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase. J Neurosci, 2007. 27(10): p. 2570-81.
4. Al-Hasani, R. and M.R. Bruchas, Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology, 2011. 115(6): p. 1363-81.
5. Muschamp, J.W., A. Van't Veer, and W.A. Carlezon, Jr., Tracking down the molecular substrates of stress: new roles for p38alpha MAPK and kappa-opioid receptors. Neuron, 2011. 71(3): p. 383-5.
6. Tejeda, H.A., T.S. Shippenberg, and R. Henriksson, The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci, 2012. 69(6): p. 857-96.
7. Yoo, J.H., I. Kitchen, and A. Bailey, The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us? Br J Pharmacol, 2012. 166(7): p. 1993-2014.
8. Schwarzer, C., 30 years of dynorphins--new insights on their functions in neuropsychiatric diseases. Pharmacol Ther, 2009. 123(3): p. 353-70.
9. Bortolato, M. and M.V. Solbrig, The price of seizure control: dynorphins in interictal and postictal psychosis. Psychiatry Res, 2007. 151(1-2): p. 139-43.
10. Sheffler, D.J. and B.L. Roth, Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol Sci, 2003. 24(3): p. 107-9.

Keywords:

Late stage, late stage AID, OPRK1, kappa, opioid, receptor, GPCR, CEREP, hERG, KCNH2 potassium voltage-gated channel, radiometric, counterscreen, receptors, transporters, ion channels, antagonist, inhibitor, inhibit, pain, analgesic, dynorphin, neuropathic pain, drug addiction, addiction, Scripps, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Protocol
Assay Overview:

The purpose of this binding assay performed by CEREP, is to determine whether the OPRK antagonist compound SID 144087319 has activity against the potassium voltage-gated channel, hERG. The assay was run in duplicate.

Protocol Summary:

The assay was a radioligand binding assay performed by CEREP. The specific ligand binding to the targets is defined as the difference between the total binding in the presence of 10 uM test compound and the nonspecific binding determined in the presence of 10 uM compound and an excess of unlabelled ligand. The results are expressed as a percent inhibition of control specific binding:

%_Inhibition = ( 100 - ( ( measured_specific_binding / control_specific_binding ) x 100 ) )

PubChem Activity Outcome and Score:

A response of less than or equal to 50% inhibition or stimulation is considered active. Negative inhibition represents a stimulation of binding.

Active compounds were given a score of 100 and inactive a score of 0.

The PubChem Activity Score range for inactive compounds is 0-0. There are no active compounds.

List of Reagents:

Reagents were provided by CEREP.
Comment
This assay was performed by CEREP.
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Average Inhibition at 10 uM (10μM**)The value of the mean of the inhibition replicates at 10 uMFloat%
2Standard DeviationThe standard deviation of the replicate inhibition valuesFloat
3Inhibition at 10 uM [1] (10μM**)Value of % Inhibition of hERG at 10 uM compound concentration.Float%
4Inhibition at 10 uM [2] (10μM**)Value of % Inhibition of hERG at 10 uM compound concentration.Float%

** Test Concentration.
Additional Information
Grant Number: R03NS053751

Data Table (Concise)
Data Table ( Complete ):     View All Data
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