The Development of Novel Photoactivatable Antagonists for the GABAA Receptor.
Doctoral thesis, UCL (University College London).
This thesis describes the development of novel photoactivatable antagonists for the GABAA receptor. GABAA receptors are ligand-gated Cl- channels belonging to the Cys-loop superfamily of ionotropic receptors, which play an important role inhibiting cell excitation in the nervous system. To date, no research has probed the mobility of native, unmutated GABAA receptors. In order to do this, we planned to design a series of molecules that could bind to the GABAA receptor covalently, causing inhibition. A brief overview of the GABAA receptor and the concept of photoaffinity labelling are outlined in the first chapter, followed by a chapter detailing our results and discussion. Firstly, our efforts focussed on the development of a lead compound. The molecule gabazine was chosen as our template, since the molecule possesses a highly specific affinity for the GABAA receptor. In our ongoing studies into the development of labelled analogues of gabazine as probes for the GABAA receptor, we discovered that a relatively minor addition to the gabazine skeleton significantly enhances its antagonist potency. The development of several new photoaffinity-labelled reagents capable of photochemically blocking the function of the GABAA receptor was subsequently explored. We were able to demonstrate that these reagents could block up to 49% of recombinant GABAA receptors in cultured cells. Finally, our efforts centered on creating an analogue incorporating a photoaffinity label in addition to a detectable tag. It is hoped that such a compound could be useful for exploring the spatial and temporal mobility of native GABAA receptors microscopically. The tools created are the first with the potential to knock out GABAA receptors in vivo, and avoid the need for any prior receptor transfection.
|Title:||The Development of Novel Photoactivatable Antagonists for the GABAA Receptor|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry|
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