Bookmark and Share
BioAssay: AID 2580

Summary assay for small molecule agonists of the APJ receptor

Currently there are no small molecule tools to investigate the biological functions of apelin and its receptor. Apelin is the endogenous peptide ligand for the G-protein coupled receptor (GPCR) APJ (angiotensin II receptor-like 1, AGTRL-1 and APLNR). Until the discovery of apelin, APJ was an orphan GPCR. APJ is coupled to Gai, and has been shown in cell culture to inhibit adenylate cyclase. The more ..
_
   
 Tested Compounds
 Tested Compounds
All(1)
 
 
Probe(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
All(1)
 
 
Probe(1)
 
 
Active(1)
 
 
AID: 2580
Data Source: Burnham Center for Chemical Genomics (BCCG-A323-APJ-Agonist-Summary-Assay)
BioAssay Type: Panel, Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-03-16
Modify Date: 2012-04-11

Data Table ( Complete ):           Probe    Active    All
Target
BioActive Compound: Chemical Probe: 1    Active: 1
Depositor Specified Assays
Show more
AIDNameTypeComment
2520uHTS identification of small molecule agonists of the APJ receptor via a luminescent beta-arrestin assayscreeningPrimary Screen
2764Single concentration confirmation of uHTS hits from a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assayscreening
488748Dose Response confirmation of uHTS hits from a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assayconfirmatory
488811SAR analysis of a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assayconfirmatory
488865Dose Response screen for agonists of Angiotensin II Receptor Type 1 to assess selectivity of uHTS small molecule agonists hits of the APJ receptorconfirmatory
488881SAR analysis of small molecule agonists of the Angiotensin II Receptor Type 1 to assess selectivity of uHTS small molecule agonists hits of the APJ receptorconfirmatory
488985SAR analysis of a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assay - Set 2confirmatory
488986SAR analysis of small molecule agonists of the Angiotensin II Receptor Type 1 to assess selectivity of uHTS small molecule agonists hits of the APJ receptor - Set 2confirmatory
492982SAR analysis of small molecule agonists of the Angiotensin II Receptor Type 1 to assess selectivity of uHTS small molecule agonists hits of the APJ receptor - Set 3confirmatory
492985SAR analysis of a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assay - Set 3confirmatory
493183SAR analysis of a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assay - Set 4confirmatory
493202SAR analysis of small molecule agonists of the Angiotensin II Receptor Type 1 to assess selectivity of uHTS small molecule agonists hits of the APJ receptor - Set 4confirmatory
504524SAR analysis of a small molecule agonists of the APJ receptor via a luminescent beta-arrestin assay - Set 5confirmatory
504532SAR analysis of small molecule agonists of the Angiotensin II Receptor Type 1 to assess selectivity of uHTS small molecule agonists hits of the APJ receptor - Set 5confirmatory
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Sanford-Burnham Medical Research Institute(SBMRI, San Diego CA)
Network: NIH Molecular Libraries Production Centers Network (MLPCN)
Grant Number: 1R21NS059422-01
Assay Provider: Dr. Layton Smith, Sanford-Sanford-Burnham Medical Research Institute

Currently there are no small molecule tools to investigate the biological functions of apelin and its receptor. Apelin is the endogenous peptide ligand for the G-protein coupled receptor (GPCR) APJ (angiotensin II receptor-like 1, AGTRL-1 and APLNR). Until the discovery of apelin, APJ was an orphan GPCR. APJ is coupled to Gai, and has been shown in cell culture to inhibit adenylate cyclase. The APJ gene encodes a receptor that most closely resembles the angiotensin receptor AT1. However, the APJ receptor does not bind angiotensin II. Underscoring the emerging importance of the apelin/APJ system, recent studies have shown that apelin reduces the extent of atherosclerotic lesions in ApoE-/- mice, and opposes the development of abdominal aortic aneurysms. Additional research has revealed that APJ forms a heterodimer with the Ang II receptor AT1, and that this complex facilitates antagonism of Ang II signaling by apelin. Despite these exciting results, there remains a multitude of unanswered questions regarding the role of apelin and APJ in physiology and pathology.
The project goal is to identify a chemical probe of apelin receptor function that transiently and reversibly activates the receptor. An agonist or potentiator of this receptor would provide a novel research tool to evaluate the role of apelin in cardiovascular and metabolic disease pathology.

This AID summarizes SBCCG's probe development efforts to identify agonists of the apelin receptor (APJ).

One potential probe was identified and a probe report has been submitted describing compound screening.

From the primary HTS and subsequent hit confirmation (AID 2520, 2764, 488748) several hit compounds were identified. Furthermore, hits were assessed for selectivity against the closely related angiotensin II receptor type-1 (AID 488865). Remaining hits were clustered into scaffolds and SAR studies were performed on compounds from several scaffolds reconfirming potency in the primary assay (AID 488811, 488985, 492985, 493183, 504524). SAR compounds were tested against the angiotensin II receptor type-1 to confirm selectivity (AID 488881, 488986, 492982, 493202, 504532). A novel scaffold was identified as an APJ receptor agonist, with CID46905036 (ML233) representing a very potent and selective member of the chemical series. This agonist compound was later nominated to probe candidacy status.

Details of protocols, compound structures, and results from the original assays can be found in PubChem at the respective AIDs listed above.
Panel Information
APJ agonist
    Data Table(Active)    Data Table(All)Show more
PID§NameSubstancePanel TargetsDescription
ActiveInactive
1ML#ML# for the compound
2AID_488985_EC50_11apelin receptor [Homo sapiens] [gi:4885057]
EC50 value determined using sigmoidal dose response equation
3AID_488985_EC50_2apelin receptor [Homo sapiens] [gi:4885057]
EC50 value determined using sigmoidal dose response equation
4AID_488985_EC50_3apelin receptor [Homo sapiens] [gi:4885057]
EC50 value determined using sigmoidal dose response equation
5AID_488985_EC50_4apelin receptor [Homo sapiens] [gi:4885057]
EC50 value determined using sigmoidal dose response equation
6AID_488986_EC50_11type-1 angiotensin II receptor [Homo sapiens] [gi:4501997]
EC50 value determined using sigmoidal dose response equation
7AID_488986_EC50_2type-1 angiotensin II receptor [Homo sapiens] [gi:4501997]
EC50 value determined using sigmoidal dose response equation
8AID_488986_EC50_3type-1 angiotensin II receptor [Homo sapiens] [gi:4501997]
EC50 value determined using sigmoidal dose response equation
9AID_488986_EC50_4type-1 angiotensin II receptor [Homo sapiens] [gi:4501997]
EC50 value determined using sigmoidal dose response equation

§ Panel component ID.
Protocol
Please see pertinent AIDs: 2520, 2764, 488748, 488811, 488865, 488881, 488985, 488986, 492982, 492985, 493183, 493202, 504524, 504532
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100.
Result Definitions
Show more
TIDNameDescriptionPID§Panel TargetsHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML#ML# for the compound1String
2AID_488985_OutcomeThe outcome for AID_4889852apelin receptor [Homo sapiens]Outcome
3AID_488985_Qualifier_1This qualifier is to be used with the next TID, AID_488985_EC50_1. If the qualifier is ""="", the EC50 result equals the value in that column. If the qualifier is "">"", the EC50 result is greater than that value. If the qualifier is ""<"", the EC50 result is smaller than that value2String
4AID_488985_EC50_1EC50 value determined using a sigmoidal dose response equation2FloatμM
5AID_488985_Qualifier_2This qualifier is to be used with the next TID, AID_488985_EC50_2. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value3apelin receptor [Homo sapiens]String
6AID_488985_EC50_2EC50 value determined using a sigmoidal dose response equation3FloatμM
7AID_488985_Qualifier_3This qualifier is to be used with the next TID, AID_488985_EC50_3. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value4apelin receptor [Homo sapiens]String
8AID_488985_EC50_3EC50 value determined using a sigmoidal dose response equation4FloatμM
9AID_488985_Qualifier_4This qualifier is to be used with the next TID, AID_488985_EC50_4. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value5apelin receptor [Homo sapiens]String
10AID_488985_EC50_4EC50 value determined using a sigmoidal dose response equation5FloatμM
11AID_488986_OutcomeThe outcome for AID_4889866type-1 angiotensin II receptor [Homo sapiens]Outcome
12AID_488986_Qualifier_1This qualifier is to be used with the next TID, AID_488986_EC50_1. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value6String
13AID_488986_EC50_1EC50 value determined using a sigmoidal dose response equation6FloatμM
14AID_488986_Qualifier_2This qualifier is to be used with the next TID, AID_488986_EC50_2. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value7type-1 angiotensin II receptor [Homo sapiens]String
15AID_488986_EC50_2EC50 value determined using a sigmoidal dose response equation7FloatμM
16AID_488986_Qualifier_3This qualifier is to be used with the next TID, AID_488986_EC50_3. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value8type-1 angiotensin II receptor [Homo sapiens]String
17AID_488986_EC50_3EC50 value determined using a sigmoidal dose response equation8FloatμM
18AID_488986_Qualifier_4This qualifier is to be used with the next TID, AID_488986_EC50_4. If the qualifier is "=", the EC50 result equals the value in that column. If the qualifier is ">", the EC50 result is greater than that value. If the qualifier is "<", the EC50 result is smaller than that value9type-1 angiotensin II receptor [Homo sapiens]String
19AID_488986_EC50_4EC50 value determined using a sigmoidal dose response equation9FloatμM
Additional Information
Grant Number: 1R21NS059422-01

Classification
PageFrom: