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In pharmacology, GABAA receptor positive allosteric modulators are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system. Unlike GABAA receptor agonists, GABAA PAMs do not bind at the same active site as the γ-Aminobutyric acid (GABA) neurotransmitter molecule: PAMs affect the receptor by binding at a different site on the protein. This is called allosteric modulation. GABA is a major inhibitory neurotransmitter in the Central nervous system. By binding it triggers the GABAA receptor to open its chloride channel to allow chlorine ions into the neuron, making the cell hyperpolarized and less likely to fire. GABAA PAMs bind to a different site and increase the effect of GABA by making the channel open more frequently or for longer when GABA binds. However, they do not have an effect if GABA or another agonist is not present. In psychopharmacology, GABAA receptor PAMs used as drugs have mainly sedative and anxiolytic effects. Examples of GABAA PAMs include alcohol (ethanol), benzodiazepines such as diazepam (Valium) and alprazolam (Xanax), Z-drugs such as zolpidem (Ambien), and the barbiturate drugs. ==History== The GABAA receptors have been historically a target of several drug treatment research. The earliest compounds were ions, like for example bromide. Barbiturates were first introduced in 1904, they were important for a treatment of psychiatric and neurological disorders of the time. They were useful in treatment of sleep disorders and were the first truly effective treatment for epilepsy. Benzodiazepines were discovered in 1950 and largely replaced the barbiturates because of larger therapeutical index.〔 At first benzodiazepines were considered to be very safe and very efficient minor tranquilizers but later they were criticized for their dependence producing effects. Currently there are several efficient benzodiazepines available and so one can be selected in relation to its dosage form, length of action, metabolic interaction and safety as needed. Benzodiazepines function by binding to the benzodiazepine site on most, but not all, GABAA receptors. GABAA modulation by benzodiazepine site agonists is self-limiting and the conductance of the channel is not higher with the presence of benzodiazepine and GABA than the conductane with the presence of only high concentration of GABA. Additionally, in the absence of GABA the presence of benzodiazepines alone does not open the chloride channel. Certain metabolites of progesterone and deoxycorticosterone are established as potent and selective positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor. Hans Selye demonstrated in the 1940 that certain pregnane steroids could cause both anesthesia and sedation but it was not until 40 years later that molecular mechanism emerged to explain the depressant effect of these steroids. In a rat brain slice preparation, the synthetic steroidal anesthetic alphaxalone (5α-pregnan-3α-ol-11,20 dione) enhanced both stimulus-evoked inhibition and the effects of exogenously applied muscimol which is a GABAA selective agonist. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「GABAA receptor positive allosteric modulator」の詳細全文を読む スポンサード リンク
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