GABA drugs

Discussion in 'Pharmacology' started by Alfa, Dec 21, 2004.

  1. Alfa

    Alfa Productive Insomniac Staff Member Administrator

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    GABA drugs
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    GABA (gamma-aminobutyric acid) is the most important inhibitory neurotransmitter in the CNS. By gating negative chloride (Cl-) ions into the interior of nerve cells, GABA inhibits the presynaptic release of neurotransmitter due to a positive voltage polarization pulse. Such inhibition is extremely common: GABA receptors can be found at 60 - 80% of CNS neurons.
    Subtypes of GABA receptors can be activated by the mushroom toxin muscimol (at the A subtype) as well as the antispasmodic amino acid baclofen (B subtype). These drugs directly mimic the action of GABA at the receptor.
    Allosteric facilitation of GABA receptors occurs at several distinct sites; the compounds which bind there are used as sedatives and anxiolytics. These compounds bend the receptor open to indirectly facilitate GABA binding.

    GABA agonists / facilitators
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    Progabide is a pro-drug which decomposes to GABA in the CNS. It crosses the blood-brain barrier, which GABA itself, being a zwitterion (doubly-ionized amino acid), does not. Vigabatrin (gamma-vinyl-GABA) inhibits GABA-aminotransferase (GABA-T), the enzyme responsible for degrading GABA in the synapse. It thus prolongs the sojourn of GABA molecules and promotes binding in this way.
    Depakote (valproic acid) seems to act on nerve membranes to reduce susceptibility to seizure. At high doses it acts like vigabatrin to inhibit GABA-T. Gabapentine is another recently marketed antiepileptic (Neurontin) that is also finding psychiatric application as a mood stabilizer. The neurological rationale for this application is that panic attacks (or mania in bipolar disorder) resemble epilepsy in that they are characterized by a pre-panic "kindling" phenomenon, characterized by repetitive neural firings, leading to a critical stage. Gabapentine may encourage production of or discourage degradation of GABA. Lamotrigine probably works by reducing release of glutamate, an excitatory neurotransmitter usually governed by the inhibitory GABA.
    Novel GABA drugs represent one of the most active areas of psychotropic research. Riluzole, for instance, is a GABA uptake inhibitor with anticonvulsant and hypnotic properties; it also blocks sodium channels and inhibits glutamate release.

    GABA antagonists
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    Flumazenil is a benzodiazepine which binds to the GABA receptor at the benzodiazepine site without deforming it so as to enhance GABA binding. It is thus a competitive antagonist to the benzodiazepine sedatives. Bicuculline is a selective GABA-A antagonist directly at the site where GABA binds.
    By contrast, the beta-carbolines, (CCE, CCB and CCM) are mild inverse agonists, i.e. they not only bind to and block the benzodiaepine site on the GABA receptor, but modify the receptor function to decrease GABA activity. They also show strong though ephemeral MAO-inhibiting ability.
    A structural extension of serotonin, chemical variants of the beta carbolines (tetrahydro forms) have been detected in human urine and milk. They occur more plentifully in various herbs, particularly passion flower, yage, B. caapi, and other herbs. Harmalaspecies are high in beta-carbolines like harmaline.
    The picrotoxin group of toxins are naturally-occurring GABA antagonists which can cause death due to convulsions. Tutin is present in some forms of poison honey.
     
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  2. TheCecil

    TheCecil Newbie

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    Great Post, i learned alot from that, especially since my main interests are substances that effect GABA and i've experienced the effects of the GABA agonists