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BioAssay: AID 746450

Positive allosteric modulation of human muscarinic M5 receptor relative to acetylcholine

This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10muM) with a structurally related isatin core that more ..
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 Tested Compounds
 Tested Compounds
All(11)
 
 
Unspecified(11)
 
 
 Tested Substances
 Tested Substances
All(11)
 
 
Unspecified(11)
 
 
 Related BioAssays
 Related BioAssays
AID: 746450
Data Source: ChEMBL (960038)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2014-05-03
Modify Date: 2014-08-23

Data Table ( Complete ):           View All Data
Target
Sequence: RecName: Full=Muscarinic acetylcholine receptor M5
Description ..   
Protein Family: Olfactory receptor
Comment ..   

Gene:CHRM5     Related Protein 3D Structures     More BioActivity Data..
Tested Compounds:
Description:
Title: Discovery of ML326: The first sub-micromolar, selective M5 PAM.

Abstract: This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10muM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30muM) and a robust 20-fold leftward shift of the ACh CRC.
(PMID: 23562060)
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Emax activity commentEmax activity commentString
2Emax standard flagEmax standard flagInteger
3Emax qualifierEmax qualifierString
4Emax published valueEmax published valueFloat%
5Emax standard valueEmax standard valueFloat%

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