Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7‐Nitroindolinyl‐ and 2‐(p‐Phenyl‐o‐nitrophenyl)propyl‐Based Photochemical Probes

ChemBioChem - Tập 17 Số 10 - Trang 953-961 - 2016
Srinivas Kantevari1,2, Stefan Passlick1, Hyung‐Bae Kwon3,4, Matthew T. Richers1, Bernardo L. Sabatini3, Graham C. R. Ellis‐Davies1
1Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, 10029 USA) graham.davies at mssm.edu
2Organic Chemistry Division II (CPC Division) CSIR—Indian Institute of Chemical Technology Hyderabad 500 007 India
3Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Cambridge, MA, 02115 USA
4Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA

Tóm tắt

AbstractNeurotransmitter uncaging, especially that of glutamate, has been used to study synaptic function for over 30 years. One limitation of caged glutamate probes is the blockade of γ‐aminobutyric acid (GABA)‐A receptor function. This problem comes to the fore when the probes are applied at the high concentrations required for effective two‐photon photolysis. To mitigate such problems one could improve the photochemical properties of caging chromophores and/or remove receptor blockade. We show that addition of a dicarboxylate unit to the widely used 4‐methoxy‐7‐nitroindolinyl‐Glu (MNI‐Glu) system reduced the off‐target effects by about 50–70 %. When the same strategy was applied to an electron‐rich 2‐(p‐Phenyl‐o‐nitrophenyl)propyl (PNPP) caging group, the pharmacological improvements were not as significant as in the MNI case. Finally, we used very extensive biological testing of the PNPP‐caged Glu (more than 250 uncaging currents at single dendritic spines) to show that nitro‐biphenyl caging chromophores have two‐photon uncaging efficacies similar to that of MNI‐Glu.

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ChemBioChem

Tập 17 Số 10

953-961

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