Allosteric modulators of GABA-A receptor
Allosteric agonists modulate the sensitivity of GABA-A receptors to GABA. They can increase or reduce GABA effect, but only compounds which increase GABA effects have been retained as drugs. They are mainly benzodiazepines, barbiturates and certain steroids.
There are two types of benzodiazepines receptors:
- increasing GABA effect, i.e. enhance opening of chloride channels. Almost all benzodiazepines used in therapeutics are agonists of these receptors. They can be regarded as openers of GABA-dependant chloride channels.
- decreasing GABA effect, i.e. inhibits opening of chloride channels, they are generally called inverse agonists.
The endogenous molecules likely to activate benzodiazepines receptors have not been clearly identified. Benzodiazepines are synthetic molecules theoretically not present in the body, although they might have been detected in certain tissues. Beta-carbolines could be endogenous ligands of benzodiazepine receptors.
Antagonists can inhibit the effects of agonists: an endogenous neuropeptide, called “diazepam binding inhibitor”, inhibits binding of benzodiazepines and their effects. Compounds of exogenous origin such as flumazenil and perhaps to a lesser degree caffeine. are also antagonists.
Receptors for barbiturates, steroid hormones such as progesterone also potentiate the response of GABA-A receptor. This is one explanation for the sedating effect of progesterone, after its transformation into alloprogesterone,.
Synthetic steroids known to be neuroactive could be of interest in treating epilepsy, insomnia and anxiety.
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