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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 ):           View Active Data    View All Data
Target
Sequence: cholinergic receptor, muscarinic 1 [Rattus norvegicus]
Description ..   
Protein Family: Olfactory receptor

Gene:CHRM1     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: Chemical Probe: 2    Active: 2
Related Experiments
AIDNameTypeComment
2425Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M1Confirmatorydepositor-specified cross reference: dose-response in calcium assay
2428Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M3Confirmatorydepositor-specified cross reference: dose-response with M3 for selectivity
2430Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-response with M2Otherdepositor-specified cross reference: dose-response with M2 for selectivity
2433Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M5Otherdepositor-specified cross reference: dose-response with M5 for selectivity
2434Discovery of novel allosteric modulators of the M1 muscarinic receptor: Acetylcholine Fold-shift Activity of PAMSConfirmatorydepositor-specified cross reference: Fold-shift assay with acetylcholine
2438Discovery of novel allosteric modulators of the M1 muscarinic receptor: PAM Calcium Assay Dose-Response with M4Confirmatorydepositor-specified cross reference: dose-response with M4 for selectivity
2626Discovery of novel allosteric modulators of the M1 Muscarinic receptor: PAM Activity with AcetylcholineScreeningdepositor-specified cross reference: stimulation of acetylcholine response
2651Discovery of Novel Allosteric Modulators of the M1 Muscarinic Receptor: PAM Calcium Assay SARConfirmatorydepositor-specified cross reference: calcium assay dose-response summary
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.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML137
PubChem Substance ID (SID) for probe 1: 8528605
PubChem Compound ID (CID) for probe 1: 4993506
Probe type for probe 1: Modulator
IC50/EC50 (nM) for probe 1: 830
Target for probe 1: M1 (gi: 18249941)
Disease relevance for probe 1: Neurodegenerative disorders
Anti-target for probe 1: M2, M3, M4, M5
Fold selectivity for probe 1: >30
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK50695/ (ID: 2377146)
Grant number for probe 1: MH077606-01
MLP Probe ML# for probe 2: ML169
PubChem Substance ID (SID) for probe 2: 85756541
PubChem Compound ID (CID) for probe 2: 44475955
Probe type for probe 2: Modulator
IC50/EC50 (nM) for probe 2: 1380
Target for probe 2: M1 (gi: 18249941)
Disease relevance for probe 2: Neurodegenerative disorders
Anti-target for probe 2: M2, M3, M4, M5
Fold selectivity for probe 2: >30
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK50704/ (ID: 2377924)
Grant number for probe 2: MH077606-01
PubMed Publication ID (PMID) for probe 1: 23237839,20156687
PubMed Publication ID (PMID) for probe 2: 23173069
NCBI Book chapter title for probe 1: Discovery and development of the a highly selective M1 Positive Allosteric Modulator (PAM)
NCBI Book chapter title for probe 2: Discovery and development of a second highly selective M1 Positive Allosteric Modulator (PAM)
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
Additional Information
Grant Number: MH077606-01

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