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L. Yue, M. Pawlowski, F. Feng, K. S. Bruzik, H. Qian, D. R. Pepperberg; Light-Regulated, Propofol-Based Potentiators of GABAA Receptors. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3301.
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© ARVO (1962-2015); The Authors (2016-present)
We recently found that propofol (2,6-diisopropyl phenol), a known potentiator of GABAA receptors, markedly enhances responses of GABAA receptors of isolated retinal bipolar cells (Yue et al., 2009 ARVO). Previous studies in a variety of sytems have demonstrated photo-regulation of physiological processes by synthetic molecules containing a photoisomerizable azobenzene group (e.g., Park & Standaert (2001) Bioorg. Med. Chem. 9:3215-3223; Fortin et al. (2008) Nature Meth. 5:331-338). We are pursuing development of light-regulated azobenzene analogs of propofol, and report here the effects of compounds of this type on responses of α1β2γ2 GABAA receptors expressed in Xenopus laevis oocytes.
The primary investigated compounds were two propofol analogs containing substituents at carbon 4 (C-4). In compound 1, the C-4 substituent consisted of a butyryl spacer coupled via an amide linkage to 4-(aminomethyl)-azobenzene-4'-carboxylic acid; compound 2 was similar to 1 but possessed an acetyl rather than butyryl spacer. Using two-electrode voltage clamp, we recorded responses to 3 µM GABA alone, vs. 3 µM GABA plus defined concentrations of 1 and 2. Trans-to-cis and cis-to-trans photoisomerizations of the analogs in solutions statically bathing the oocyte were driven with UV (365 nm) and white light, respectively.
For both 1 and 2, absorbance spectra of the trans- and cis-dominated forms closely resembled those of unsubstituted azobenzene. Under conditions favoring the trans isomer, 1 µM of compound 1 strongly potentiated the GABA response (potentiation factor: 4.0 ± 1.2; n=4). UV illumination, which drove formation of the cis isomer, reduced the potentiation factor to 1.4 ± 0.2. Subsequent exposure to bright white light (generation of trans) increased the potentiation factor to 3.1 ± 0.7. Generally similar results were obtained with 10 µM of compound 1, and with 5 and 50 µM of 2.
The results demonstrate, in a model cell system, photo-control of GABAA receptors by diffusible, photo-recyclable modulators based on propofol's structure. The results encourage investigation of these compounds in preparations of retinal bipolar cells, as well as other types of neurons. As freely diffusible compounds, and potentially as receptor-tethered compounds, the present and further optimized propofol analogs may be valuable as components of future molecular therapies for vision restoration in retinal degenerative diseases, as well as in studies of GABAA receptor mechanisms.
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