Synthesis of an anionically substituted nitroindoline-caged GABA reagent that has reduced affinity for GABA receptors

A 7-nitroindolin-1-yl amide of the neuroactive amino acid gamma-aminobutryate (GABA) has been synthesised with two phosphate groups attached to the indoline nucleus at 4-alkoxy substituent. The compound is designed to release GABA on a sub-microsecond time scale in response to flash photolysis with near-UV light. The presence of the high negatively charged substituent shows evidence that interaction of the GABA conjugate with ionotropic GABA receptors is much reduced in comparison with an earlier nitroindoline-GABA compound that had no charged groups on the indoline nucleus. In experiments to develop the eventual synthetic route, an unusual reductive cleavage of a TBDMS ether was observed as a significant side reaction during reduction of an indole to an indoline with NaBH3CN in glacial acetic acid. In the eventual synthetic route, the primary amine of GABA was masked as an azide until the final stage of the synthesis, which overcame significant problems with other forms of amine protection. (c) 2007 Elsevier Ltd. All rights reserved.