Bookmark and Share
BioAssay: AID 2665

Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: SAR with Acetylcholine

Screening Center Name & PI: Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters, C. David Weaver ..more
_
   
 Tested Compounds
 Tested Compounds
All(114)
 
 
Active(72)
 
 
Inactive(42)
 
 
 Tested Substances
 Tested Substances
All(114)
 
 
Active(72)
 
 
Inactive(42)
 
 
AID: 2665
Data Source: Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters (M5 PAM SAR)
BioAssay Type: Primary, Primary Screening, Single Concentration Activity Observed
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2010-03-24
Modify Date: 2010-07-12

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compounds: 72
Related Experiments
Show more
AIDNameTypeComment
2186Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: Fold-shift AssayConfirmatorydepositor-specified cross reference
2192Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: [3H]N-methylscopolamine CompetitionConfirmatorydepositor-specified cross reference
2194Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: [3H]N-methylscopolamine Competition with AcetylcholineConfirmatorydepositor-specified cross reference
2198Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: PAM SAR with Muscarinic M5Otherdepositor-specified cross reference
2204Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: Calcium Flux AssayConfirmatorydepositor-specified cross reference
2206Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5: SAR with Muscarinic M1Otherdepositor-specified cross reference
2416Discovery of Novel Allosteric Modulators of the Muscarinic Receptor M5Summarydepositor-specified cross reference
626Discovery of Novel Allosteric Modulators of the M1 Muscarinic Receptor: Agonist Primary ScreenScreeningsame project related to Summary assay
651776Discovery of Novel Positive Allosteric Modulators (PAM) of the Muscarinic Receptor M5: Fold-shift AssayConfirmatorysame project related to Summary assay
Description:
Assigned Assay Grant Number: MH077606-1
Screening Center Name & PI: Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters, C. David Weaver
Chemistry Center Name & PI: Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley
Assay Submitter & Institution: P. Jeffrey Conn, Vanderbilt University


Muscarinic acetylcholine receptors are family A GPCRs comprised of five distinct mammalian subtypes (mAChR1-5 or M1-M5), which are expressed differentially throughout the body and play an important role in a variety of physiological processes. Among the mAChRs, M1 and M4 have been historically considered attractive targets for small molecule treatments of numerous CNS disorders such as Alzheimer's disease and schizophrenia due to their respective localization and involvement in regulation of certain aspects of learning, memory, sleep, motor control, reward, and pain, among others. However, discovery of subtype-selective small molecules has proven highly difficult due to the conservation of the orthosteric binding-site across the mAChRs. This has contributed to the failure of muscarinic agonists in clinical trials and has also hampered pharmacological investigation into the role(s) of each mAChR in basic neurobiology.

Among the mAChRs, M5 has remained perhaps the most challenging to investigate pharmacologically due in part to its extremely low expression level and a complete lack of M5-selective ligands. Interestingly, studies using M5-KO mice suggest that M5 is the sole mediator of acetylcholine-induced cerebrovasodilation, which has led to the hypothesis that an M5 activator would have therapeutic efficacy in treatment of cerebrovascular dementias and ischemic stroke. Furthermore, M5-KO mice show dramatically reduced reward responses to drugs of abuse, consistent with its putative localization on midbrain dopaminergic neurons of the nigrostriatal and mesolimbic pathways. This suggests that M5 antagonism or negative modulation may have utility in treatment of illicit drug addiction and withdrawal. Despite these and other related findings from M5-KO mice, there remains a strong need for small molecule tools to probe M5 function and test M5-related hypotheses in order to advance the state of the mAChR research field and provide critical proof-of-concept studies for drug discovery aims.
Protocol
Compounds were tested at 30uM (fixed) in the presence of a submaximal concentration of acetylcholine (ACh) (~EC10) and evaluated for their ability to elevate the response to ACh in rM1- or hM5-expressing CHO cells using the primary calcium assay.
Compounds eliciting a response less than approximately 40 %ACh Max in either or both cell line were scored as inactive (0). Compounds eliciting a response between approximately 40 and 60 %ACh Max in either or both cell lines were scored as partially active (50). Compounds eliciting a response greater than approximately 60 %ACh Max in either or both cell lines were considered fully active (100).
Result Definitions
TIDNameDescriptionAnnotationHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1VUIDVanderbilt University registration numberString
2M1 Protein GImuscarinic acetylcholine receptor m1 [Rattus norvegicus]Protein target giString
3M1 %ACh Max (30μM**)Activity as a percent of the maximal acetylcholine response at muscarinic M1 receptorFloat
4M5 Protein GImuscarinic acetylcholine receptor M5 [Homo sapiens]Protein target giString
5M5 %ACh Max (30μM**)Activity as a percent of the maximal acetylcholine response at muscarinic M5 receptorFloat

** Test Concentration.
Additional Information
Grant Number: MH077606-1

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