Charters, Abigail Rachel; (1993) Chemical synthesis and biochemical studies on derivatives of the GABAA receptor antagonist, RU5135. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The GABAA receptors are fast-acting, ligand-gated chloride ion channels whose function can be allosterically modulated by several classes of therapeutically important drugs such as benzodiazepines, barbiturates and neurosteroids. The GABAA receptors constitute a large gene family and several complementary DNAs which encode GABAA receptor subunits have been cloned. Consequently, it has emerged that the mammalian central nervous system may contain several pharmacological subclasses of GABAA receptors. The characterisation of these subclasses may contribute to the formation of therapeutically selective agents which modulate GABAA receptor function. The amidine steroid, RU5135, is a competitive, high affinity antagonist of the GABAA receptor and the strychnine-sensitive glycine receptor. The compound contains two chemically functional groups which have permitted the synthesis of novel, pharmacologically active derivatives of RU5135. These were isolated by flash chromatography and thin layer chromatography and their structures were analysed by proton nuclear magnetic resonance spectroscopy and electron impact mass spectroscopy. The N- and O-derivatives of RU5135 were investigated to determine their respective potencies at membrane-bound GABAA and glycine receptors and detergent-solubilised GABAA receptors from bovine brain by the use of radioligand inhibition binding assays. The synthetic derivatives were subsequently immobilised to Sepharose and the resultant RU5135 affinity matrices were characterised with respect to their ability to isolate GABAA receptors from sodium deoxycholate detergent extracts of bovine cerebral cortex.

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