The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−). Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl− will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).
Tiletamine is a dissociative anesthetic and pharmacologically classified as an NMDA receptor antagonist. It is related chemically to ketamine. Tiletamine hydrochloride exists as odorless white crystals.
Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.
DMCM is a drug from the β-carboline family. It acts as a negative allosteric modulator of GABAA receptors, meaning that it causes the opposite effects to the benzodiazepine class of drugs. As such, DMCM has anxiogenic and convulsant properties, and is used in scientific research to induce anxiety so that new anxiolytic medications can be tested, and to produce convulsions so that anticonvulsant medications can be tested. It has also been shown to produce analgesic effects in animals, thought to be because it produces panic which reduces the perception of pain.
Ro15-4513(IUPAC: Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate) is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in the 1980s. It acts as a inverse agonist, and can therefore be an antidote to the acute impairment caused by alcohols, including ethanol, isopropanol, tert-butyl alcohol, tert-amyl alcohol, 3-methyl-3-pentanol, methylpentynol and ethchlorvynol.
FG-7142 (ZK-31906) is a drug which acts as a partial inverse agonist at the benzodiazepine allosteric site of the GABAA receptor. It has anorectic, anxiogenic and pro-convulsant effects. It also increases release of acetylcholine and noradrenaline, and improves memory retention in animal studies.
Panadiplon (U-78875) is an anxiolytic drug with a novel chemical structure that is not closely related to other drugs of this type. It has a similar pharmacological profile to the benzodiazepine family of drugs, but with mainly anxiolytic properties and relatively little sedative or amnestic effect, and so is classified as a nonbenzodiazepine anxiolytic.
Saripidem is a sedative and anxiolytic drug in the imidazopyridine family, which is related to the better known drugs zolpidem and alpidem.
Pipequaline (INN) is an anxiolytic drug that was never marketed. It possesses a novel chemical structure that is not closely related to other drugs of this type. The drug has a similar pharmacological profile to the benzodiazepine family of drugs, but with mainly anxiolytic properties and very little sedative, amnestic or anticonvulsant effects, and so is classified as a nonbenzodiazepine anxiolytic.
Gamma-aminobutyric acid (GABA) A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the GABRA5 gene.
L-655,708 (FG-8094) is a nootropic drug invented in 1996 by a team working for Merck, Sharp and Dohme, that was the first compound developed which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor. It acts as an inverse agonist at the α1, α2, α3 and α5 subtypes, but with much higher affinity for α5, and unlike newer α5 inverse agonists such as α5IA, L-655,708 exerts its subtype selectivity purely via higher binding affinity for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to.
Suritozole is an investigational cognition enhancer. It acts as a partial inverse agonist at the benzodiazepine receptor site on the GABAA ion channel complex, but does not have either anxiogenic or convulsant effects, unlike other BZD inverse agonists such as DMCM. It was investigated for the treatment of depression and Alzheimer's disease, but clinical development seems to have been discontinued.
SH-053-R-CH3-2′F is a drug used in scientific research which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more subtype-selective than most other drugs of this class, having high selectivity, binding affinity and efficacy at the α5 subtype of the GABAA receptor. This gives much tighter control of the effects produced, and so while SH-053-R-CH3-2′F retains sedative and anxiolytic effects, it does not cause ataxia at moderate doses. SH-053-R-CH3-2′F also blocks the nootropic effects of the α5-selective inverse agonist PWZ-029, so amnesia is also a likely side effect.
PWZ-029 is a benzodiazepine derivative drug with nootropic effects developed by WiSys, It acts as a subtype-selective, mixed agonist-inverse agonist at the benzodiazepine binding site on the GABAA receptor, acting as a partial inverse agonist at the α5 subtype and a weak partial agonist at the α3 subtype. This gives it a mixed pharmacological profile, producing at low doses memory-enhancing effects but with no convulsant or anxiogenic effects or muscle weakness, although at higher doses it produces some sedative effects.
ZK-93423 is an anxiolytic drug from the β-Carboline family, closely related to abecarnil. It is a nonbenzodiazepine GABAA agonist which is not subtype selective and stimulates α1, α2, α3, and α5-subunit containing GABAA receptors equally. It has anticonvulsant, muscle relaxant and appetite stimulating properties comparable to benzodiazepine drugs. ZK-93423 has also been used as a base to develop new and improved beta-carboline derivatives and help map the binding site of the GABAA receptor.
Divaplon (RU-32698) is a nonbenzodiazepine, anxiolytic and anticonvulsant drug from the pyrazolopyrimidine family of drugs. It acts as a partial agonist at the "benzodiazepine site" of the GABAA receptor in the brain.
Terbequinil (SR-25776) is a stimulant and nootropic drug which acts as a partial inverse agonist at benzodiazepine sites on the GABAA receptor. In human trials it was found to partially reverse the sedative and amnestic effects of the hypnotic drug triazolam with only slight effects when administered by itself.
FG-8205 (L-663,581) is an imidazobenzodiazepine derivative related to bretazenil, which acts as a partial agonist at GABAA receptors, with slight selectivity for the α1-containing subtype. In animal tests it has anxiolytic and anticonvulsant effects but with little sedation or ataxia produced.
Iomazenil is an antagonist and partial inverse agonist of benzodiazepine and a potential treatment for alcohol use disorder. The compound was introduced in 1989 by pharmaceutical company Hoffmann-La Roche as an Iodine-123-labelled SPECT tracer for imaging benzodiazepine receptors in the brain. Iomazenil is an analogue of flumazenil (Ro15-1788).
Radequinil is a cognitive enhancer which acts as a partial inverse agonist of the benzodiazepine site of the GABAA receptor. It was under development by Dainippon Sumitomo Pharma for the treatment of Alzheimer's disease and made it to phase II clinical trials but development seems to have been halted and it was never marketed.
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