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BioAssay: AID 2079

Summary of Image-based HTS for Selective Antagonists of GPR35

Addictive behavior stems from abnormal signaling activities in the brain. Thus identification of compounds blocking this modified signaling activity may lead to treatments for addictive behavior. GPR35, a to-date uncharacterized orphan G-Protein Coupled Receptor, is thought to play a role in addiction and has homology to other known receptors of abuse. The goal of this project is to identify small molecule antagonists of GPR35, which may aid in characterization of this receptor and ultimately further the understanding of the role of GPR35 in addictive behavior. ..more
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 Tested Compounds
 Tested Compounds
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
 Tested Substances
 Tested Substances
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
AID: 2079
Data Source: Burnham Center for Chemical Genomics (BCCG-A259-GPR35-Antagonist-Summary-Assay)
BioAssay Type: Panel, Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-10-29
Modify Date: 2012-04-11

Data Table ( Complete ):           View Data Probes    View Active Data    View All Data
Target
BioActive Compounds: Chemical Probe: 3    Active: 3
Related Experiments
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AIDNameTypeComment
2058Image-Based HTS for Selective Antagonists of GPR35Confirmatorydepositor-specified cross reference: Image-Based HTS for Selective Antagonists of GPR35
2397SAR Analysis of Selective Antagonists of GPR55 using an Image-Based AssayConfirmatorydepositor-specified cross reference: SAR Analysis of Selective Antagonists of GPR55 using an Image-Based Assay
2480SAR analysis of Antagonists of the GPR35 Receptor using an Image-Based Assay - Set 2Confirmatorydepositor-specified cross reference: SAR analysis of Antagonists of the GPR35 Receptor using an Image-Based Assay - Set 2
463201SAR Analysis using an Image-based Vasopressin Agonist Counter Assay for the Identification of Selective Antagonists of the GPR35 ReceptorOtherdepositor-specified cross reference: SAR Analysis using an Image-based Vasopressin Agonist Counter Assay for the Identification of Select
463202SAR Analysis using an Image-based Vasopressin Antagonist Counter Assay for the Identification of Selective Antagonists of the GPR35 ReceptorOtherdepositor-specified cross reference: SAR Analysis using an Image-based Vasopressin Antagonist Counter Assay for the Identification of Sel
463217SAR Analysis for the identification of Selective Antagonists of ERK1/2 Activity in GPR35-Overexpressing U2OS CellsConfirmatorydepositor-specified cross reference: SAR Analysis for the identification of Selective Antagonists of ERK1/2 Activity in GPR35-Overexpress
463227SAR analysis of Antagonists of the GPR35 Receptor using an Image-Based Assay - Set 5Confirmatorydepositor-specified cross reference: SAR analysis of Antagonists of the GPR35 Receptor using an Image-Based Assay - Set 5
463228SAR Analysis of Selective Antagonists of GPR55 using an Image-Based Assay - Set 3Confirmatorydepositor-specified cross reference: SAR Analysis of Selective Antagonists of GPR55 using an Image-Based Assay - Set 3
488987SAR Analysis for the identification of Selective Antagonists of ERK1/2 Activity in GPR35-Overexpressing U2OS Cells - Set 2Confirmatorydepositor-specified cross reference: SAR Analysis for the identification of Selective Antagonists of ERK1/2 Activity in GPR35-Overexpress
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 Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1X01MH085708-01
Assay Provider: Dr. Lawrence Barak, Duke University

Addictive behavior stems from abnormal signaling activities in the brain. Thus identification of compounds blocking this modified signaling activity may lead to treatments for addictive behavior. GPR35, a to-date uncharacterized orphan G-Protein Coupled Receptor, is thought to play a role in addiction and has homology to other known receptors of abuse. The goal of this project is to identify small molecule antagonists of GPR35, which may aid in characterization of this receptor and ultimately further the understanding of the role of GPR35 in addictive behavior.

This AID summarizes SBCCG's probe development efforts to identify antagonists of the orphan receptor GPR35.

Three potential probes have been identified and probe reports have been submitted describing compound screening.

From the primary HTS and subsequent hit confirmation (AID 2058) several hit compounds were identified. Hits were clustered into scaffolds and SAR studies were performed on compounds from several scaffolds reconfirming potency (AID 2480). Compounds were further tested for selectivity against the related orphan receptor GPR55 (AID 2397). Three novel scaffolds were identified as GPR35 antagonists with CID2286812 (ML145) representing the very potent and selective probe for chemical series 1, CID1542103 (ML144) representing the potent and selective probe for chemical series 2, and CID9581011 (ML194) representing chemical series 3 with intermediate potency between the first two probes.

The probes were characterized further by two assays performed in the assay provider's and his collaborator's laboratories. Selectivity against an unrelated receptor Vasopressin IIa was evaluated for ML144 and ML145 in agonist (AID 463201) and antagonist (AID 463202) mode showing that neither probe agonizes nor antagonizes the vasopressin receptor. Additionally, downstream ERK1/2 phosphorylation activity of the probe compounds was determined (AID 463217) using an "in-cell" Western assay concluding that all three probes have measurable activity downstream in the authentic signaling pathway.

Details of protocols, compound structures, and results from the original assays can be found in PubChem at the respective AIDs listed below.
Panel Information
GPR35_Panel
    Data Table(Active)    Data Table(All)Show more
PID§NameSubstancePanel TargetsDescription
ActiveInactive
1ML#ML# for the compound
2AID_2480_IC50_12G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
3AID_2480_IC50_2G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
4AID_2480_IC50_3G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
5AID_2397_IC50_11G-protein coupled receptor 55 [Homo sapiens] [gi:33695107]
IC50 value determined using sigmoidal dose response equation
6AID_2397_IC50_2G-protein coupled receptor 55 [Homo sapiens] [gi:33695107]
IC50 value determined using sigmoidal dose response equation
7AID_463217_IC50_111G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
8AID_463201_%_Activation_11vasopressin V2 receptor isoform 1 [Homo sapiens] [gi:4557345]
%Activation for the data set
9AID_463201_%_Activation_2vasopressin V2 receptor isoform 1 [Homo sapiens] [gi:4557345]
%Activation for the data set
10AID_463227_IC50_11G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
11AID_463227_IC50_2G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
12AID_463227_IC50_3G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
13AID_488987_IC50_11G-protein coupled receptor 35 isoform a [Homo sapiens] [gi:33695097]
IC50 value determined using sigmoidal dose response equation
14AID_463228_IC50_11G-protein coupled receptor 55 [Homo sapiens] [gi:33695107]
IC50 value determined using sigmoidal dose response equation
15AID_463228_IC50_2G-protein coupled receptor 55 [Homo sapiens] [gi:33695107]
IC50 value determined using sigmoidal dose response equation

§ Panel component ID.
Protocol
Please see pertinent AIDs: 2058, 2397, 2480, 463201, 463202, 463217, 463227, 463228, 488987
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100.
Result Definitions
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TIDNameDescriptionPID§Panel TargetsHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML#ML# for the compound1String
2AID_2480_OutcomeThe outcome for AID_24802G-protein coupled receptor 35 isoform a [Homo sapiens]Outcome
3AID_2480_Qualifier_1This qualifier is to be used with the next TID, AID_2480_IC50_1. If the qualifier is ""="", the IC50 result equals the value in that column. If the qualifier is "">"", the IC50 result is greater than that value. If the qualifier is ""<"", the IC50 result is smaller than that value2String
4AID_2480_IC50_1IC50 value determined using a sigmoidal dose response equation2FloatμM
5AID_2480_Qualifier_2This qualifier is to be used with the next TID, AID_2480_IC50_2. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value3G-protein coupled receptor 35 isoform a [Homo sapiens]String
6AID_2480_IC50_2IC50 value determined using a sigmoidal dose response equation3FloatμM
7AID_2480_Qualifier_3This qualifier is to be used with the next TID, AID_2480_IC50_3. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value4G-protein coupled receptor 35 isoform a [Homo sapiens]String
8AID_2480_IC50_3IC50 value determined using a sigmoidal dose response equation4FloatμM
9AID_2397_OutcomeThe outcome for AID_23975G-protein coupled receptor 55 [Homo sapiens]Outcome
10AID_2397_Qualifier_1This qualifier is to be used with the next TID, AID_2397_IC50_1. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value5String
11AID_2397_IC50_1IC50 value determined using a sigmoidal dose response equation5FloatμM
12AID_2397_Qualifier_2This qualifier is to be used with the next TID, AID_2397_IC50_2. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value6G-protein coupled receptor 55 [Homo sapiens]String
13AID_2397_IC50_2IC50 value determined using a sigmoidal dose response equation6FloatμM
14AID_463217_OutcomeThe outcome for AID_4632177G-protein coupled receptor 35 isoform a [Homo sapiens]Outcome
15AID_463217_Qualifier_1This qualifier is to be used with the next TID, AID_463217_IC50_1. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value7String
16AID_463217_IC50_1IC50 value determined using a sigmoidal dose response equation7FloatμM
17AID_463201_OutcomeThe outcome for AID_4632018vasopressin V2 receptor isoform 1 [Homo sapiens]Outcome
18AID_463201_%_Activation_1% Activation in AID_4632018Float
19AID_463201_%_Activation_2% Activation in AID_4632019vasopressin V2 receptor isoform 1 [Homo sapiens]Float
20AID_463227_OutcomeThe outcome for AID_46322710G-protein coupled receptor 35 isoform a [Homo sapiens]Outcome
21AID_463227_Qualifier_1This qualifier is to be used with the next TID, AID_463227_IC50_1. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value10String
22AID_463227_IC50_1IC50 value determined using a sigmoidal dose response equation10FloatμM
23AID_463227_Qualifier_2This qualifier is to be used with the next TID, AID_463227_IC50_2. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value11G-protein coupled receptor 35 isoform a [Homo sapiens]String
24AID_463227_IC50_2IC50 value determined using a sigmoidal dose response equation11FloatμM
25AID_463227_Qualifier_3This qualifier is to be used with the next TID, AID_463227_IC50_3. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value12G-protein coupled receptor 35 isoform a [Homo sapiens]String
26AID_463227_IC50_3IC50 value determined using a sigmoidal dose response equation12FloatμM
27AID_488987_OutcomeThe outcome for AID_48898713G-protein coupled receptor 35 isoform a [Homo sapiens]Outcome
28AID_488987_Qualifier_1This qualifier is to be used with the next TID, AID_488987_IC50_1. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value13String
29AID_488987_IC50_1IC50 value determined using a sigmoidal dose response equation13FloatμM
30AID_463228_OutcomeThe outcome for AID_46322814G-protein coupled receptor 55 [Homo sapiens]Outcome
31AID_463228_Qualifier_1This qualifier is to be used with the next TID, AID_463228_IC50_1. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value14String
32AID_463228_IC50_1IC50 value determined using a sigmoidal dose response equation14FloatμM
33AID_463228_Qualifier_2This qualifier is to be used with the next TID, AID_463228_IC50_2. If the qualifier is "=", the IC50 result equals the value in that column. If the qualifier is ">", the IC50 result is greater than that value. If the qualifier is "<", the IC50 result is smaller than that value15G-protein coupled receptor 55 [Homo sapiens]String
34AID_463228_IC50_2IC50 value determined using a sigmoidal dose response equation15FloatμM
Additional Information
Grant Number: 1X01MH085708-01

Classification
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