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BioAssay: AID 2385

Probe Development Summary for Identification of Novel General Anesthetics

Anesthetic development has remained a largely empirical process. There are growing concerns about the cognitive effects of known general anesthetics [1] and acceleration of the onset of neurodegenerative disease [2]. The compounds' toxicity [3] and multiple specific binding targets in the mammalian brain [4] has made them less attractive as drug leads. ..more
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AID: 2385
Data Source: NCGC (APOF100)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2010-02-19
Target
Sequence: Chain A, Horse Spleen Apoferritin
Description ..   
Protein Family: Ferritin iron storage proteins

Related Protein 3D Structures     More BioActivity Data..
Related Experiments
AIDNameTypeComment
2323qHTS Validation Assay for Identification of Novel General AnestheticsConfirmatorydepositor-specified cross reference: qHTS Validation Assay for Identification of Novel General Anesthetics
485281qHTS Assay for Identification of Novel General AnestheticsConfirmatorydepositor-specified cross reference
489008Confirmation Assay for Identification of Novel General AnestheticsConfirmatorydepositor-specified cross reference
624098Assay for General Anesthetic Phenotype in Xenopus TadpolesScreeningdepositor-specified cross reference
624122Isothermal Titration Calorimetry Based Assay for Measurement of Binding Affinity to ApoferritinConfirmatorydepositor-specified cross reference
Description:
Anesthetic development has remained a largely empirical process. There are growing concerns about the cognitive effects of known general anesthetics [1] and acceleration of the onset of neurodegenerative disease [2]. The compounds' toxicity [3] and multiple specific binding targets in the mammalian brain [4] has made them less attractive as drug leads.

In the primary screen for this project, a GABAergic mimetic model system, apoferritin and a profluorescent 1-aminoanthracene ligand (1-AMA), is used to construct a competitive binding assay for identification of novel general anesthetics [5], [6].

This project is currently ongoing. Additional details of follow-up assays and results will be summarized here in future updates.

References:

[1] S.L. Bianchi, T. Tran, C. Liu, S. Lin, Y. Li, J.M. Keller, R.G. Eckenhoff, and M.F. Eckenhoff, Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiol Aging 29 (2008) 1002-10.

[2] Z. Xie, Y. Dong, U. Maeda, R.D. Moir, W. Xia, D.J. Culley, G. Crosby, and R.E. Tanzi, The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci 27 (2007) 1247-54.

[3] P. Honegger, and J.M. Matthieu, Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures. J Neurosci Res 45 (1996) 631-6.

[4] M.F. Eckenhoff, K. Chan, and R.G. Eckenhoff, Multiple specific binding targets for inhaled anesthetics in the mammalian brain. J Pharmacol Exp Ther 300 (2002) 172-9.

[5] C.A. Butts, J. Xi, G. Brannigan, A.A. Saad, S.P. Venkatachalan, R.A. Pearce, M.L. Klein, R.G. Eckenhoff, and I.J. Dmochowski, Identification of a fluorescent general anesthetic, 1-aminoanthracene. Proc Natl Acad Sci U S A 106 (2009) 6501-6.

[6] W.A. Lea, J. Xi, A. Jadhav, L. Lu, C.P. Austin, A. Simeonov, and R.G. Eckenhoff, A high-throughput approach for identification of novel general anesthetics. PLoS One 4 (2009) e7150.

Source: NIH Chemical Genomics Center [NCGC]
Assay Submitter: Roderic Eckenhoff, University of Pennsylvania
Screening Center PI: Christopher P. Austin, NIH
Probe Development: NIH Chemical Genomics Center [NCGC]
NIH Grant Number: MH084836-01
Protocol
Please see related BioAssays for all protocols relevant to this probe development project: 2323
Comment
Compound ranking comments will be added here as small molecule probes are developed and are annotated with bioassays in PubChem.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML306
PubChem Substance ID (SID) for probe 1: 134419032
PubChem Compound ID (CID) for probe 1: 5070704
Probe type for probe 1: Modulator
IC50/EC50 (nM) for probe 1: 3040
Target for probe 1: Apoferritin (gi: 254220970)
Disease relevance for probe 1: Surgery
Anti-target for probe 1: In Vivo Tadpole Toxicity
Fold selectivity for probe 1: >90
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK153223/ (ID: 3046460)
Grant number for probe 1: MH084836
NCBI Book chapter title for probe 1: Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System
Additional Information
Grant Number: MH084836-01

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