The synthesis and biochemical and pharmacological evaluation of gamma-aminobutyric acid antagonists

McLaughlin, Neil James (1981) The synthesis and biochemical and pharmacological evaluation of gamma-aminobutyric acid antagonists. Doctoral thesis, City of London Polytechnic.


Y-Aminobutyrio acid has been shown to be a major inhibitory neurotransmitter in the central nervous system (CNS). This study is concemed with the examination of a number of GABA antagonists in two in vitro assay systems.

A series of cage-structured compounds including bicyolic phosphate esters (2,6,7,-Trioxa-l-phosphabicyclo (2,2,2,) octan-l-oxides with suitable 4-substituents) have been shown to be potent a GABA antagonists. These compounds do not act directly on the postsysnaptio GABA receptor site but probably at the same site as another potent GABA antagonist piorotoxinin. It has been shown that the substituent group on the bridge-head on the 4-carbon atom in the molecule plays a very important role in the toxic potency and GABA antagonistic properties of these compounds. A very bulky and branched substituent caused a great increase in potency. This property was utilised in the synthesis of a series of these compounds.

The binding of radiolabelled ligands (both agonists and antagonists) to synaptic membrane fractions can be utilised as a convenient assay for the study of GABA receptors. Such assays using frozen--thawed rat brain synaptosomal membranes has been demonstrated to be stereospecific and saturable using (3H)-GABA, the potent GABA agonist (3H)-muscimol also with GABA antagonists using (3H)-bicuculline methobromide and (3H)-dihydropicrotoxinin. Utilising these methods a number of agonists and antagonists have been examined to evaluate their ability to displace the stereospecific binding. The synthesised GABA antagonists have also been used to evaluate their properties on the depolarising effect of on the rat superior cervical ganglion in comparison to results obtained by known GABA, antagonists.

The bicyclic phosphate esters were shown to be very toxic when administered to mammals causing seizures and death, this effect being attributed to the antagonism of GABA in the CNS. They were shown to be potent inhibitors of GABA in the superior cervical ganglion. In binding studios with (3H)-muscimol they did not displace any of the bound agonist and also were shown not to displace bound (3H)-dihydropicrotoxinin. The results obtained in this study have been discussed and compared with structure-activity relationships to other compounds of similar structure.

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