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BioAssay: AID 1785

Summary of small molecule antagonists of the kappa opioid receptor

Drug addiction is a disease originating in the central nervous system that produces compulsive behaviors despite the negative consequences that may result. Major addictive drugs of abuse include components of tobacco, opiates, marijuana, ethanol, cocaine, and derivatives of amphetamines. While the addictive behaviors produced by these substances may be generally similar, the drugs act at more ..
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 Tested Compounds
 Tested Compounds
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Probe(2)
 
 
Active(2)
 
 
 Tested Substances
 Tested Substances
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Probe(2)
 
 
Active(2)
 
 
AID: 1785
Data Source: Burnham Center for Chemical Genomics (BCCG-A206-KOR-Antagonist-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-05-27
Modify Date: 2011-06-22

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compounds: Chemical Probe: 2    Active: 2
Related Experiments
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AIDNameTypeComment
1778uHTS identification of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assayConfirmatorydepositor-specified cross reference: uHTS identification of small molecule antagonists of the kappa opioid receptor via a luminescent bet
1966HTS Dose response counterscreen for assays utilizing the enzyme, b-galactosidaseConfirmatorydepositor-specified cross reference: HTS Dose response counterscreen for assays utilizing the enzyme, b-galactosidase
2136HTS Image-Based Screen for Selective Antagonists of the KOR ReceptorConfirmatorydepositor-specified cross reference: HTS Image-Based Screen for Selective Antagonists of the KOR Receptor
2285SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assayConfirmatorydepositor-specified cross reference: SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arres
2344HTS Image-Based Screen for Agonists of the MOR ReceptorConfirmatorydepositor-specified cross reference
2348SAR analysis of Antagonists of the Kappa Opioid Receptor (KOR) using an Image-Based AssayConfirmatorydepositor-specified cross reference: SAR analysis of Antagonists of the Kappa Opioid Receptor (KOR) using an Image-Based Assay
2352SAR Analysis of Agonists of the MOR Receptor using an Image-Based AssayConfirmatorydepositor-specified cross reference
2356HTS Image-Based Screen for Antagonists of the DOR ReceptorConfirmatorydepositor-specified cross reference: HTS Image-Based Screen for Antagonists of the DOR Receptor
2357SAR Analysis of Antagonists of the DOR Receptor using an Image-Based AssayConfirmatorydepositor-specified cross reference: SAR Analysis of Antagonists of the DOR Receptor using an Image-Based Assay
2359SAR analysis of Agonists of the Kappa Opioid Receptor (KOR) using an Image-Based AssayConfirmatorydepositor-specified cross reference
2370SAR Analysis of Agonists of the DOR Receptor using an Image-Based AssayConfirmatorydepositor-specified cross reference
2420SAR Analysis of Antagonists of the MOR Receptor using an Image-Based AssayConfirmatorydepositor-specified cross reference: SAR Analysis of Antagonists of the MOR Receptor using an Image-Based Assay
2478SAR Analysis of Antagonists of the MOR Receptor using an Image-Based Assay - Set 2Confirmatorydepositor-specified cross reference
2491SAR analysis of Antagonists of the Kappa Opioid Receptor (KOR) using an Image-Based Assay - Set 2Confirmatorydepositor-specified cross reference: SAR analysis of Antagonists of the Kappa Opioid Receptor (KOR) using an Image-Based Assay - Set 2
2492SAR Analysis of Agonists of the MOR Receptor using an Image-Based Assay - Set 2Confirmatorydepositor-specified cross reference
2493SAR Analysis of Agonists of the DOR Receptor using an Image-Based Assay - Set 2Confirmatorydepositor-specified cross reference
2495SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 2Confirmatorydepositor-specified cross reference
2498SAR Analysis of Antagonists of the DOR Receptor using an Image-Based Assay - Set 2Confirmatorydepositor-specified cross reference
2500SAR analysis of small molecule agonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 2Confirmatorydepositor-specified cross reference
434981SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 3Confirmatorydepositor-specified cross reference
449737SAR analysis of small molecule agonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 3Confirmatorydepositor-specified cross reference
463105SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 4Confirmatorydepositor-specified cross reference
488819SAR analysis of Antagonists of the Kappa Opioid Receptor (KOR) using an Image-Based Assay - Set 3Confirmatorydepositor-specified cross reference
488822SAR Analysis of Agonists of the MOR Receptor using an Image-Based Assay - Set 3Confirmatorydepositor-specified cross reference
488826SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 5Confirmatorydepositor-specified cross reference
488831SAR Analysis of Antagonists of the DOR Receptor using an Image-Based Assay - Set 3Confirmatorydepositor-specified cross reference
488842SAR Analysis of Antagonists of the MOR Receptor using an Image-Based Assay - Set 3Confirmatorydepositor-specified cross reference
488925SAR analysis of Antagonists of the Kappa Opioid Receptor (KOR) using an Image-Based Assay - Set 4Confirmatorydepositor-specified cross reference
488935SAR analysis of small molecule antagonists of the kappa opioid receptor via a luminescent beta-arrestin assay - Set 6Confirmatorydepositor-specified cross reference
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Production Centers Network (MLPCN)
Grant Number: 1X01DA026208-01
Assay Provider: Dr. Lawrance Barak , Duke University, Durham NC

Drug addiction is a disease originating in the central nervous system that produces compulsive behaviors despite the negative consequences that may result. Major addictive drugs of abuse include components of tobacco, opiates, marijuana, ethanol, cocaine, and derivatives of amphetamines. While the addictive behaviors produced by these substances may be generally similar, the drugs act at different receptor sites in the brain. Recent studies have shown that opioid receptors play a role regulating the addictive behaviors of other receptors that interact with illicit and legal substances of abuse. Opioid receptors are composed of multiple subtypes whose contributions to addictive behaviors are not fully delineated. Moreover, different compounds acting at a single receptor type may produce dissimilar behaviors due to variations in their chemical structures. Thus, both for delineating the biology and signaling ability of each receptor and for developing novel therapies, it would be desirable to identify multiple small molecule ligands that target a given receptor subtype. This entails expanding the chemical space about each of the receptors as variations in receptor conformations due to distinct ligand structures affect receptor signaling behaviors, and consequently physiological responsiveness. Morphine is a prime example of an opioid ligand with distinctive signaling properties.

The specific aim of this project is to identify subtype specific small molecule agonists of the human kappa opioid receptor (KOR). These compounds can be optimized to provide the pharmacological means to precisely control the signaling of their specific target receptor subtype. This work thus provides the addiction field both novel research tools and potential therapeutic scaffolds.

This AID summarizes SBCCG's probe development efforts to identify antagonists of the kappa opioid receptor (KOR).

From the primary HTS and subsequent hit confirmation (AID 1778) several hit compounds were identified. Hits were clustered into scaffolds and SAR studies were performed on compounds from several scaffolds reconfirming potency (AID 2285). Antagonist activity was further confirmed for these compounds via image-based high content assays (AID 2348). Compounds were further tested for selectivity against the related delta (AID 2357) and mu opioid receptors (AID 2420). A novel scaffold was identified as a KOR antagonist, with CID3342390 (ML140) representing a very potent and selective member of the chemical series. This antagonist compound was later nominated to probe candidacy status.

As second novel more potent antagonist (120 nM by DiscoveRx) for the kappa opioid (KOP) receptor that is >267-fold selective over the mu(MOP) and the delta(DOP) opioid receptors is CID44665680 (ML190). Importantly, this probe and its analogs represent a novel chemical class compared to current literature antagonists and our previously submitted probe, ML140. Accordingly, this probe and its analogues may serve as interesting tools to advance addiction research. Additionally, this new chemotype is less complicated compared to known KOP receptor antagonist compounds. The structure contains no stereochemical centers and the short, versatile synthetic route enables both the synthesis of potential analogs and the production of the compound on larger scale.



Details of protocols, compound structures, and results from the original assays can be found in PubChem at the respective AIDs listed below.
Protocol
Please see pertinent AIDs: 1778, 1966, 2136, 2285, 2348, 2356, 2357, 2420, 2478, 2491, 2495, 2498, 434981, 463105, 488819, 488826, 488831, 488842, 488925, 488935
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100. Compound SIDs 87218794 and 88442997 have been identified as probe molecules.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML140
PubChem Substance ID (SID) for probe 1: 87218794
PubChem Compound ID (CID) for probe 1: 3342390
Probe type for probe 1: Antagonist
IC50/EC50 (nM) for probe 1: 850
Target for probe 1: KOR (gi: 39725940)
Disease relevance for probe 1: Addiction
Anti-target for probe 1: MOR, DOR
Fold selectivity for probe 1: >40
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK50689/ (ID: 2376474)
Grant number for probe 1: DA026208-01
MLP Probe ML# for probe 2: ML190
PubChem Substance ID (SID) for probe 2: 88442997
PubChem Compound ID (CID) for probe 2: 44665680
IC50/EC50 (nM) for probe 2: 120
Target for probe 2: KOP kappa-opioid receptor (Dx) (gi: 39725940)
Anti-target for probe 2: MOP and DOP
Fold selectivity for probe 2: >267
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK66151/ (ID: 2647372)
Grant number for probe 2: DA026208-01
NCBI Book chapter title for probe 1: Selective KOP Receptor Antagonists: Probe 1
NCBI Book chapter title for probe 2: Antagonist for the Kappa Opioid Receptor
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML#ML# for the compoundString
Additional Information
Grant Number: 1X01DA026208-01

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