GABAA receptor positive allosteric modulator

Fig 1. Chemical structure of gamma-aminobutyric acid or GABA

Fig 2. Schematic diagram of a GABAA receptor protein ((α1)2(β2)2(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl-) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.

In pharmacology, GABA_A receptor positive allosteric modulators, also known as GABAkines or GABA_A receptor potentiators,^[1] are positive allosteric modulator (PAM) molecules that increase the activity of the GABA_A receptor protein in the vertebrate central nervous system.

GABA is a major inhibitory neurotransmitter in the central nervous system. Upon binding, it triggers the GABA_A receptor to open its chloride channel to allow chloride ions into the neuron, making the cell hyperpolarized and less likely to fire. GABA_A PAMs increase the effect of GABA by making the channel open more frequently or for longer periods. However, they have no effect if GABA or another agonist is not present.

Unlike GABA_A receptor agonists, GABA_A PAMs do not bind at the same active site as the γ-aminobutyric acid (GABA) neurotransmitter molecule: they affect the receptor by binding at a different site on the protein. This is called allosteric modulation.

In psychopharmacology, GABA_A receptor PAMs used as drugs have mainly sedative and anxiolytic effects. Examples of GABA_A PAMs include ethanol, benzodiazepines such as diazepam (Valium) and alprazolam (Xanax), Z-drugs such as zolpidem (Ambien) and the barbiturate drugs.