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Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7‐Nitroindolinyl‐ and 2‐( p ‐Phenyl‐ o ‐nitrophenyl)propyl‐Based Photochemical Probes
Author(s) -
Kantevari Srinivas,
Passlick Stefan,
Kwon HyungBae,
Richers Matthew T.,
Sabatini Bernardo L.,
EllisDavies Graham C. R.
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600019
Subject(s) - chemistry , nitro , chromophore , glutamate receptor , biphenyl , photodissociation , photochemistry , neurotransmitter , receptor , biophysics , biochemistry , organic chemistry , biology , alkyl
Neurotransmitter 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.