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BioAssay: AID 652045

Summary of the probe development efforts to identify antagonists of the kappa 1 (OPRK1) opioid receptor

Name: Summary of the probe development efforts to identify antagonists of the kappa 1 (OPRK1) opioid receptor. ..more
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AID: 652045
Data Source: The Scripps Research Institute Molecular Screening Center (OPRK1_ANT_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-02-15
Modify Date: 2013-03-18
Target
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)
652075Late-stage results from the probe development effort to identify antagonists of OPRK1: radiometric-based biochemical hERG counterscreen assayOtherdepositor-specified cross reference: Late-stage counterscreen (hERG activity in duplicate)
652076Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based biochemical cytochrome P450 inhibition assayOtherdepositor-specified cross reference: Late-stage assay (cytochrome P450 inhibition)
652077Late-stage fluorescence-based cell-based dose response assay for antagonists of kappa opioid receptor 1 (OPRK1)Confirmatorydepositor-specified cross reference: Late-stage dose response (OPRK1 antagonists in triplicate)
652078Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based pharmacokinetic plasma protein binding assayOtherdepositor-specified cross reference: Late-stage assay (plasma protein binding)
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)Confirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (S1P1 antagonists in triplicate)
652080Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response OPRD1 counterscreen, Set 2Confirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRD1 antagonists in triplicate)
652081Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response OPRM1 counterscreen, Set 2Confirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRM1 antagonists in triplicate)
652082Fluorescence-based cell-based confirmation assay for antagonists of kappa opioid receptor 1 (OPRK1)Otherdepositor-specified cross reference: Confirmation assay (OPRK1 antagonists in triplicate)
652083Late-stage results from the probe development effort to identify antagonists of OPRK1: CEREP radiometric-based biochemical counterscreen panel assayOtherdepositor-specified cross reference: Late-stage counterscreen (CEREP panel)
652084Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response assay, Set 2.Confirmatorydepositor-specified cross reference: Late-stage dose response (OPRK1 antagonists 8 replicates)
652085Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based in vivo plasma and brain levelsOtherdepositor-specified cross reference: Late-stage assay (in vivo plasma and brain levels)
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 compoundsConfirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (cytotoxicity in quadruplicate)
652087Counterscreen for antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based assay to identify antagonists of Sphingosine 1-Phosphate Receptor 1 (S1P1)Otherdepositor-specified cross reference: Counterscreen (S1P1 antagonists in triplicate)
652088Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based biochemical hepatic microsome stability assayOtherdepositor-specified cross reference: Late-stage assay (hepatic microsome stability)
652108Late-stage results from the probe development effort to identify antagonists of OPRK1: In vivo tail flick assayOtherdepositor-specified cross reference: Late-stage assay (In vivo tail flick assay)
652113Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based parallel artificial membrane permeability (PAMPA) assayOtherdepositor-specified cross reference: Late-stage assay (permeability)
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: OPRK1_ANT_SUMMARY

Name: Summary of the probe development efforts to identify antagonists of the kappa 1 (OPRK1) opioid receptor.

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.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of antagonists the kappa 1 (OPRMK)opioid receptor. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

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:

Summary, Summary AID, OPRK1, kappa, opioid, receptor, GPCR, beta-arrestin, U2OS, Tangotrade mark, beta-lactamase, FRET, FRET-enabled substrate, TEV, TEV protease, beta-arrestin, EC80 challenge, SNC80, antagonist, inhibitor, inhibit, pain, analgesic, dynorphin, neuropathic pain, drug addiction, addiction, 384, Scripps, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN
Additional Information
Grant Number: R03NS053751

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