Antagonists of GABA

This dual activity against both nematode and arthropod parasites of animals was an unexpected bonus from a screen for anthelmintic agents. The reason for this broad activity lies in their mode of action. They act by interfering with y-aminobutyric acid (GABA) mediated neurotransmission. When treated with avermectin, the nematode Ascaris suum becomes paralyzed although it retains normal muscle tone (17). Picrotoxin, an antagonist of GABA, can reverse the effect of avermectin on neurotransmission vitro. 

Non-benzodiazepine hypnotic aipha 1 isoform antagonist of GABA-A/ benzodiazepine receptors... 

Macdonald RL, Barker JL. Pentylenetetrazol and penicillin are selective antagonists of GABA-mediated post-synaptic inhibition in cultured mauunahau neurones. Nature 1977 267(5613) 720-1. 

Figure 1. Similar actions of PTX and a bicycloorthocarboxylate at 5 yM (+) as antagonists of GABA-mediated relaxation events in the cockroach coxal depressor muscle. Transient relaxation events in the muscle, shown as downward deflections, are caused by brief trains of 8-Hz stimuli applied every 10 s to GABA-ergic inhibitory motorneurons. A saline wash (+) permits recovery.

Bicuculine an antagonist of GABA and synaptic inhibition of the spinal cord of the cat. Brain Res. 33 57 (1971). 

Corey reported a highly efficient cyclization of unsaturated diacid 239 in the presence of Pb(OAc)4 (Scheme 9.33) [173, 174). The resulting dilactone 240 (99 % yield) was subsequently recruited in the total synthesis of picrotox-inin (241), an antagonist of GABA inhibition at synapses [173]. 

There are many studies on the induction and spread of spiking in animals both in vivo and in isolated brain slices, generally initiated by the use of GABA antagonists or removal of Mg + ions in vitro). Unfortunately since neither of these events is likely to occur in or around a human epileptic focus the results do not tell us much about how focal activity arises and spreads in humans. This needs to be achieved by the use of human epileptic tissue even though the procedures found to control experimentally induced spiking may well be applicable to humans. 

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