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.
Acamprosate, sold under the brand name Campral, is a medication which reduces alcoholism cravings. It is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for alcohol use disorder in most individuals, as it only addresses withdrawal symptoms and not psychological dependence. It facilitates a reduction in alcohol consumption as well as full abstinence when used in combination with psychosocial support or other drugs that address the addictive behavior.
Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.
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 that induces anxiety and convulsions by acting as a negative allosteric modulator of GABAA receptors — functionally opposite to benzodiazepines and related drugs which are positive allosteric modulators — and is used in scientific research for these properties to test new anxiolytic and anticonvulsant medications, respectively. It has also been shown to produce analgesic effects in animals, which is thought to be the drug's induced panic reducing the perception of pain.
Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.
Etifoxine, sold under the trade name Stresam among others, is a nonbenzodiazepine anxiolytic agent, primarily indicated for short-term management of adjustment disorder, specifically instances of situational depression accompanied by anxiety, such as stress-induced anxiety. Administration is by mouth. Side effects associated with etifoxine use include slight drowsiness, headache, skin eruptions, and allergic reactions. In rare cases, etifoxine has been linked to severe skin and liver toxicity, as well as menstrual bleeding between periods. Unlike benzodiazepines, etifoxine does not cause sedation or lack of coordination. Etifoxine acts as a GABAA receptor positive allosteric modulator and as a ligand for translocator proteins. Both mechanisms are conjectured to contribute to its anxiolytic properties.
Etazolate (SQ-20,009, EHT-0202) is an anxiolytic drug which is a pyrazolopyridine derivative and has unique pharmacological properties. It acts as a positive allosteric modulator of the GABAA receptor at the barbiturate binding site, as an adenosine antagonist of the A1 and A2 subtypes, and as a phosphodiesterase inhibitor selective for the PDE4 isoform. It is currently in clinical trials for the treatment of Alzheimer's disease.
LY-404187 is an AMPA receptor positive allosteric modulator which was developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of AMPA receptor potentiators.
CGP-7930 was the first positive allosteric modulator of GABAB receptors described in literature. CGP7930 is also a GABAA receptor positive allosteric modulator and a blocker of Potassium channels.
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.
LY-487,379 is a drug used in scientific research that acts as a selective positive allosteric modulator for the metabotropic glutamate receptor group II subtype mGluR2. It is used to study the structure and function of this receptor subtype, and LY-487,379 along with various other mGluR2/3 agonists and positive modulators are being investigated as possible antipsychotic and anxiolytic drugs.
NS-11394 is a drug which acts as a subtype-selective positive allosteric modulator at GABAA receptors, with selectivity for the α3 and α5 subtypes. It has been researched as an analgesic for use in chronic or neuropathic pain.
In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.
Zuranolone, sold under the brand name Zurzuvae, is a medication used for the treatment of postpartum depression. It is taken by mouth.
Mevidalen (developmental code name LY-3154207) is a dopaminergic drug which is under development for the treatment of Lewy body disease, including those with Parkinson's disease. It acts as a selective positive allosteric modulator (PAM) of the dopamine D1 receptor. The drug is orally active and crosses the blood–brain barrier. It is a tetrahydroisoquinoline and is a close analogue of DETQ, another D1 receptor PAM. Mevidalen has been found to have wakefulness-promoting effects in sleep-deprived humans. Side effects of mevidalen have been reported to include increased heart rate and blood pressure, insomnia, dizziness, nausea, vomiting, anxiety, nervousness, fatigue, headaches, palpitations, and contact dermatitis, as well as falls in those with dementia. As of March 2022, mevidalen is in phase 2 clinical trials for the treatment of Lewy body disease. Besides for movement disorders and dementia, D1 receptor PAMs like mevidalen might have value in the treatment of certain neuropsychiatric disorders, such as depression, excessive somnolence, and attention deficit hyperactivity disorder.
Darigabat is a GABAergic medication which is under development for the treatment of photosensitive epilepsy, focal onset seizures, panic disorder, and other anxiety disorders. It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued. It is taken via oral administration.
Deuterated etifoxine is a deuterated drug which is under development for the treatment of anxiety disorders and mood disorders.
KRM-II-81 is a positive allosteric modulator of the GABAA receptor. It is selective for the alpha2 and alpha3 subunits. KRM-II-81 displays anxiolytic, antidepressant and anticonvulsant effects. However, it has less adverse effects than some other GABAA PAMs: it has low to no sedation and no tolerance development.
