This project serves to contribute to our understanding of the pharmacology of the general anesthetic propofol through the use of a photoactive analogue, meta-azi-propofol. The mechanisms of propofol-induced hypnosis remain unclear on both molecular and systems neuroscience levels. Further, propofol and other general anesthetics are becoming increasingly recognized as mediators of neurodevelopmental and neurodegenerative risks with the potential for causing irreversible phenotypes. Meta-azi-propofol contains a diazirine moiety that undergoes photolysis when exposed to long wave ultraviolet light (~370 nm) to create a reactive carbene intermediate. Novel techniques involving localized stimulation of meta-azi-propofol in vivo will elucidate brain regions that contribute to the unconsciousness produced by this general anesthetic. Comprehensive in vitro proteomic experiments with meta-azi-propofol will uncover molecular substrates that potentially contribute to alkylphenol anesthesia and the acute and long-term side effects associated with these anesthetic compounds. Further, the identification of protein binding sites of meta-azi-propofol through photolabeling and tandem mass spectrometry techniques will provide insight into binding specificity in order to improve our understanding of drug action by these small hydrophobic molecules. By addressing these aims, the knowledge gained will add to our appreciation for the widespread impact of general anesthetics within the central nervous system and will generate areas for future research to minimize the harmful potential of these widely used drugs.

Public Health Relevance

Every year general anesthetics are administered to millions of people in America and abroad despite a clear understanding of the mechanisms that govern their clinical usefulness. Additionally, concern has risen regarding the ability of these compounds to cause developmental deficiencies in the central nervous system of the young and to accelerate neurodegenerative processes in the elderly. The optimal usage of currently available drugs and the prospect for the development of improved general anesthetics relies on our ability to discern the pharmacology of these compounds.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F15-P (20))
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Silberberg, Shai D
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University of Pennsylvania
Schools of Medicine
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Ren, Xianfeng; Schmidt, William; Huang, Yiyuan et al. (2018) Fropofol decreases force development in cardiac muscle. FASEB J 32:4203-4213
Meng, Tao; Bu, Weiming; Ren, Xianfeng et al. (2016) Molecular mechanism of anesthetic-induced depression of myocardial contraction. FASEB J 30:2915-25
Woll, Kellie A; Weiser, Brian P; Liang, Qiansheng et al. (2015) Role for the propofol hydroxyl in anesthetic protein target molecular recognition. ACS Chem Neurosci 6:927-35
Weiser, Brian P; Hall, Michael A; Weinbren, Nathan L et al. (2015) Macroscopic and macromolecular specificity of alkylphenol anesthetics for neuronal substrates. Sci Rep 5:9695
Weiser, Brian P; Eckenhoff, Roderic G (2015) Propofol inhibits SIRT2 deacetylase through a conformation-specific, allosteric site. J Biol Chem 290:8559-68
Weiser, Brian P; Woll, Kellie A; Dailey, William P et al. (2014) Mechanisms revealed through general anesthetic photolabeling. Curr Anesthesiol Rep 4:57-66
Weiser, Brian P; Bu, Weiming; Wong, David et al. (2014) Sites and functional consequence of VDAC-alkylphenol anesthetic interactions. FEBS Lett 588:4398-403
Weiser, Brian P; Salari, Reza; Eckenhoff, Roderic G et al. (2014) Computational investigation of cholesterol binding sites on mitochondrial VDAC. J Phys Chem B 118:9852-60
Weiser, Brian P; McCarren, Hilary S (2013) Disinhibition of histaminergic neurons: lack of effect on arousal switch following propofol hypnosis. J Neurosci 33:1295-6
Weiser, Brian P; Kelz, Max B; Eckenhoff, Roderic G (2013) In vivo activation of azipropofol prolongs anesthesia and reveals synaptic targets. J Biol Chem 288:1279-85

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