The synthesis and pharmacology of gamma-aminobutyric acid receptor mimetics

McDonald, Jane Anne Margaret (1981) The synthesis and pharmacology of gamma-aminobutyric acid receptor mimetics. Doctoral thesis, City of London Polytechnic.


Gamma-aminobutyric acid (GABA) has been shown to be an important inhibitory neurotransmitter in mammalian central nervous system (CNS). GABA receptors have been previously characterized in mammalian brain using 3H-GABA itself, a potent GABA agonist, 3H-muscimol, and the GABA antagonist, 3H-bicuculline methiodide. Recently, it has been suggested that 1,2,3,6 Tetrahydropyridine-4-carboxylic acid (Isoguvacine) is a potent GABA receptor agonist. It has also been reported to act as a mixed agonist/antagonist at the GABA-benzodiazepine receptor complex.

The binding of 3H-Isoguvacine to frozen-thawed, rat brain synaptosomal membranes has been investigated and found to be saturable, specific and stereospecific. The pharmacology of this 3H-Isoguvacine binding site was seen to be consistent with an interaction at the postsynaptic GABA receptor site. The effects of detergent treatment on this binding site-were investigated and indicated a single site, both in control and in Triton X-lOO treated membranes.

A series of benzodiazepines were shown to displace 3H-Isoguvacine bound to frozen-thawed rat synaptosomal membranes. This effect was shown to be temperature-dependent and could be blocked by picrotoxinin (10-4 M). Pentobarbitone was also seen to displace 3H-Isoguvacine binding, albeit at high IC5O values; an effect antagonized by picrotoxinin. Neither the benzodiazepines nor pentobarbitone had any effect on 3H-GABA binding in frozen-thawed membranes.

In contrast, using fresh rat synaptosomal membranes, neither the benzodiazepines nor pentobarbitone had any effect on 3H-Isoguvacine binding, whereas both were shown to potentiate 3H-GABA binding.

A series of conformationally-restricted analogues of GABA have been synthesized and tested using two in vitro assay systems, viz. the rat superior cervical ganglion and a radioligand binding assay. These studies revealed that the class of GABA agonist, in which the amino groups are incorporated into six-membered rings exhibit an unexpected variety of activities with respect to their ability to inhibit 3H-GABA binding; their affinity for GABA uptake sites and their interaction with the coupled GABA/benzodiazepine sites.

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