The goal of the Chemistry Core is to provide a complete support of the PPG activities in terms of access to synthetic molecular probes to be used for the investigation of general anesthetic binding sites of ligand-gated receptors of y-aminobutyric acid (GABAA) acetylcholine and serotonin . The probes will represent analogs of four major classes of anesthetics that interact with these receptors, and will be used for studying the corresponding multiple binding sites on these receptors. The most important aspects of our structural and synthetic design is to produce photoactivatable analogs with minimal structure alteration to retain high binding affinity and to ensure the analogous modes of binding to those of the parent molecules, and to permit synthesis of the radiolabeled molecules with the highest specific radioactivity possible. We will synthesize analogs of the following groups of receptor ligands: (i) propofol, a GABAA receptor ligand and a potent clinically used general anesthetic;(ii) barbituric acid, a ligand of GABAA and nicotinic acetylcholine receptors; (iii) long-chain aliphatic and aromatic alcohols, ligands that have binding sites on all members of the superfamily;and (iv) etomidate, another potent ligand that binds in the anesthetic site of GABAA receptors. In addition, when needed, we will resynthesize any needed ligand that has previously been used by the PPG. The leadership of the Core has been assumed by Dr. Bruzik in Chicago. A small part of the Core remains at MGH for the distribution and maintenance of stocks of existing photolabels. Administratively, the Core is structured with the Program Director as PI and a subcontract to the University of Illinois, Chicago.

Public Health Relevance

(See Instmctions):

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM058448-15
Application #
8532919
Study Section
Special Emphasis Panel (ZGM1-PPBC-0)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
15
Fiscal Year
2013
Total Cost
$209,499
Indirect Cost
$67,833
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Eaton, Megan M; Germann, Allison L; Arora, Ruby et al. (2016) Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol. Curr Neuropharmacol 14:772-80
Zhang, Xi (2016) Instant Integrated Ultradeep Quantitative-structural Membrane Proteomics Discovered Post-translational Modification Signatures for Human Cys-loop Receptor Subunit Bias. Mol Cell Proteomics 15:3665-3684
Forman, Stuart A; Miller, Keith W (2016) Mapping General Anesthetic Sites in Heteromeric γ-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes. Anesth Analg 123:1263-1273
Chiara, David C; Jounaidi, Youssef; Zhou, Xiaojuan et al. (2016) General Anesthetic Binding Sites in Human α4β3δ γ-Aminobutyric Acid Type A Receptors (GABAARs). J Biol Chem 291:26529-26539
Amlong, Corey A; Perkins, Mark G; Houle, Timothy T et al. (2016) Contrasting Effects of the γ-Aminobutyric Acid Type A Receptor β3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R-mTFD-MPAB. Anesth Analg 123:1241-1246
Ziemba, Alexis M; Forman, Stuart A (2016) Correction for Inhibition Leads to an Allosteric Co-Agonist Model for Pentobarbital Modulation and Activation of α1β3γ2L GABAA Receptors. PLoS One 11:e0154031
Nourmahnad, Anahita; Stern, Alex T; Hotta, Mayo et al. (2016) Tryptophan and Cysteine Mutations in M1 Helices of α1β3γ2L γ-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site. Anesthesiology 125:1144-1158
Forman, Stuart A; Chiara, David C; Miller, Keith W (2015) Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors. Neuropharmacology 96:169-77
Hamouda, Ayman K; Wang, Ze-Jun; Stewart, Deirdre S et al. (2015) Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor. Mol Pharmacol 88:1-11
Liu, K; Jounaidi, Y; Forman, S A et al. (2015) Etomidate uniquely modulates the desensitization of recombinant α1β3δ GABA(A) receptors. Neuroscience 300:307-13

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