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BioAssay: AID 2543

Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Summary

Selective M1 activation is an attractive therapeutic approach for the treatment of cognitive impairment, Alzheimer's disease, schizophrenia and a number of other CNS disorders. Until recently, no highly selective M1 activators existed, and those that claimed to be highly M1 selective were either not centrally penetrant or possessed significant ancillary pharmacology which prohibited their use as more ..
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Probe(2)
 
 
Active(2)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Probe(2)
 
 
Active(2)
 
 
AID: 2543
Data Source: Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters (M1 PAM Sum)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Screening Center Network
BioAssay Version:
Deposit Date: 2010-03-13
Modify Date: 2010-05-28

Data Table ( Complete ):           Active    All
Target
Sequence: cholinergic receptor, muscarinic 1 [Rattus norvegicus]
Description ..   
Protein Family: Serpentine type 7TM GPCR chemoreceptor Srx

Gene:CHRM1     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: Chemical Probe: 2    Active: 2
Depositor Specified Assays
AIDNameTypeComment
2425Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M1confirmatorydose-response in calcium assay
2434Discovery of novel allosteric modulators of the M1 muscarinic receptor: Acetylcholine Fold-shift Activity of PAMSconfirmatoryFold-shift assay with acetylcholine
2433Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M5otherdose-response with M5 for selectivity
2438Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M4confirmatorydose-response with M4 for selectivity
2428Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M3confirmatorydose-response with M3 for selectivity
2430Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-response with M2otherdose-response with M2 for selectivity
2651Discovery of Novel Allosteric Modulators of the M1 Muscarinic Receptor: PAM Calcium Assay SARconfirmatorycalcium assay dose-response summary
2626Discovery of novel allosteric modulators of the M1 Muscarinic receptor: PAM Activity with Acetylcholinescreeningstimulation of acetylcholine response
Description:
Assay Provider: P. Jeffery Conn
Assay Provider Affiliation: Vanderbilt University
Grant Title: Discovery of novel allosteric modulators of the M1 Muscarinic receptor
Grant Number: 1 R03 MH077606-01

Selective M1 activation is an attractive therapeutic approach for the treatment of cognitive impairment, Alzheimer's disease, schizophrenia and a number of other CNS disorders. Until recently, no highly selective M1 activators existed, and those that claimed to be highly M1 selective were either not centrally penetrant or possessed significant ancillary pharmacology which prohibited their use as probes to study M1 receptor function. We have identified that different M1 PAM chemotypes display different modes of activity on downstream receptor signaling. Thus, all allosteric M1 activation is not equivalent, and additional tool compounds representing diverse chemotypes are required to truly dissect and study M1 function in the CNS.

Probe Summary:
The probe (SID 85286053; External ID: VU0366369-1) was identified as muscarinic M1 positive allosterica modulator (PAM) and declared as a probe molecule. This unique M1 PAM chemotype should allow for in vitro molecular pharmacology and electrophysiology experiments to study the receptor trafficking profile and role of selective M1 receptor activation. This probe possesses high selectivity versus M2-M5, as well as a large panel of GPCRs, ion channels and transporters. SID 85286053 is moderately centrally penetrant (B/P ratio is 0.22), and while in vivo studies are possible, it has not been optimized for CNS penetration. SID 85286053 also displays reasonable solubility in acceptable vehicles (>5 mg/mL) in 20% beta-cyclodextrin and >100 uM in DMSO.

The probe (SID 85756541; External ID: VU0405652-1) was declared a second M1 PAM and thus declared a probe. This molecule can be used for in vitro molecular pharmacology and electrophysiology experiments to study the receptor trafficking profile and the role of selective M1 receptor activation by this unique M1 PAM chemotype. Use of this probe alongside our initial M1 PAM probe (SID 85286053) could improve our understanding of the M1 signaling pathway and elucidate the difference, if any, between high and low Ach fold-shift compounds, due to their different pharmacological characteristics. This probe possesses high selectivity versus M2-M5, as well as a large panel of GPCRs, ion channels and transporters. While in vivo studies are possible, it has not been investigated for such uses.
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
Additional Information
Grant Number: MH077606-01

Data Table (Concise)
Classification
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