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. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions and, to a lesser extent, bicarbonate ions.
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.
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 an 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.
QH-II-66 (QH-ii-066) is a sedative drug which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more selective than most other drugs of this class and so produces somewhat less sedation and ataxia than other related drugs such as diazepam and triazolam, although it still retains anticonvulsant effects.
L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme.
SL651498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed 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.
ELB-139 (LS-191,811) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
TPA-023 (MK-0777) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a mixed, subtype-selective ligand of the benzodiazepine site of α1, α2, α3, and α5-containing GABAA receptors, where it acts as a partial agonist at benzodiazepine sites of the α2 and α3-containing subtypes, but as a silent antagonist at α1 and α5-containing subtypes. It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.
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.
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.
TB-21007 is a nootropic drug which acts as a subtype-selective inverse agonist at the α5 containing GABAA receptors.
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.
Ro4938581 is a nootropic drug invented in 2009 by a team working for Hoffmann-La Roche, which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor. It has good selectivity for the α5 subtype and did not produce convulsant or anxiogenic effects in animal studies, making it a promising potential nootropic. Ro4938581 and a related derivative basmisanil have subsequently been investigated for the alleviation of cognitive dysfunction in Down syndrome.
MRK-016 is a selective α5 subunit-containing GABAA negative allosteric modulator, that has nootropic properties. It has been found to produce rapid, ketamine-like antidepressant effects in animal models of depression.
A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). They are closely related and similar to GABAA receptor antagonists. The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.
SH-I-048A (SH-i-048A) is a benzodiazepine derivative related in structure to compounds such as flubromazepam and meclonazepam. SH-I-048A is described as a non subtype selective superagonist at the benzodiazepine site of GABAA receptors, with a binding affinity of 0.77 nM at the α1 subtype, 0.17 nM at α2, 0.38 nM at α3 and 0.11 nM at α5. It has been used to study the functional differences between the different subtypes of the GABAA receptor.
GL-II-73 (GL-ii-073) is a benzodiazepine derivative related in chemical structure to compounds such as midazolam and adinazolam. It is described as an α5 preferring positive allosteric modulator of the benzodiazepine site of GABAA receptors, with weaker activity at α2 and α3 and no significant affinity for the α1 subtype. In animal tests it was found to produce effects consistent with antidepressant, anxiolytic and nootropic actions.
α3IA, also known as GTPL4094, is an inverse agonist of the GABAA receptor. It is more selective for the α3 subunit, hence its name.
