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 (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).
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.
Melanocortin receptors are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors.
PK-11195 is an isoquinoline carboxamide which binds selectively to the peripheral benzodiazepine receptor (PBR). It is one of the most commonly used PBR ligands due to its high affinity for the PBR in all species, although it is starting to be replaced by newer and more selective ligands.
The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the SIGMAR1 gene.
Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. In humans, the translocator protein is encoded by the TSPO gene. It belongs to a family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR to transport cholesterol into mitochondria, though evidence is mixed.
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.
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.
Emapunil is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. This protein has multiple functions, among which is regulation of steroidogenesis, particularly the production of neuroactive steroids such as allopregnanolone in the brain. In both animal and human trials, emapunil produced fast acting anxiolytic and anti-panic effects, without producing sedation or withdrawal symptoms following cessation of use. Emapunil is also used in its 11C radiolabelled form to map the distribution of TSPO receptors in the brain.
FGIN-1-27 is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. It is thought to produce anxiolytic effects by stimulating steroidogenesis of neuroactive steroids such as allopregnanolone.
FGIN-1-43 is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. It is thought to produce anxiolytic effects by stimulating steroidogenesis of neuroactive steroids such as allopregnanolone, and is several times more potent than the related drug FGIN-127.
SSR-180,575 is a drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. It has been shown to have neuroprotective and cardioprotective effects and to stimulate steroidogenesis of pregnenolone in the brain, which may be linked to its neuroprotective action.
DAA-1097 is a drug which acts as a potent and selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO, but with no affinity at central benzodiazepine receptors. It has anxiolytic effects in animal studies.
Ro5-4864 (4'-chlorodiazepam) is a drug which is a benzodiazepine derivative of diazepam. However unlike most benzodiazepine derivatives, Ro5-4864 lacks affinity for GABAA receptors and lacks typical benzodiazepine effects, instead being sedative yet also convulsant and anxiogenic in effects. Ro5-4864 was found to be a potent ligand for the "peripheral benzodiazepine receptor", later renamed to mitochondrial translocator protein 18kDa (TSPO). Despite its convulsant effects, at lower doses Ro5-4864 has proved to be neuroprotective and has become widely used for research into the role of the TSPO protein in neurotoxicity. In vitro studies and rodent models also suggest the possibility of analgesic, antidepressant, cardioprotective, and anti-cancer effects.
MGS-0039 is a drug that is used in neuroscientific research, which acts as a potent and selective antagonist for group II of the metabotropic glutamate receptors (mGluR2/3). It produces antidepressant and anxiolytic effects in animal studies, and has been shown to boost release of dopamine and serotonin in specific brain areas. Research has suggested this may occur through a similar mechanism as that suggested for the similarly glutamatergic drug ketamine.
DPA-714 or N,N-diethyl-2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide is a selective ligand for the translocator protein (TSPO) currently under evaluation for several clinical applications. For this reason, a practical, multigram synthetic route for its preparation has been described.
DPA-713 or N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide is a selective ligand for the translocator protein (TSPO).
NE-100 or 4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine is a selective sigma-1 receptor antagonist, with a reported binding affinity of Ki = 1.03 ± 0.01 nM, and more than 205 times selectivity over the sigma-2 receptor.
GML-1 is a TSPO ligand with anxiolytic activity. Its binding affinity to TSPO is comparable with PK11195. GML-1 is selective for TSPO versus the central benzodiazepine receptor. The compound GML-1 was the most active of a series of 1-arylpyrrolo[1,2-a]pyrazine-3-carboxamides, and its anxiolytic effects were examined using the open field test (OFT) and the elevated plus maze (EPM) test. The EPM test is a general anxiety test measuring the time spent by animals in the open or the enclosed arms. When compound was administered to CD-1 mice at the dose of 1.0 mg/kg, it significantly increased the percentage of open arm entries and the time spent in the open arms. GML-1 is a potential antianxiety agent.
Julie C. Price is an American medical physicist and professor of radiology at Massachusetts General Hospital (MGH), Harvard Medical School (HMS), as well as the director of PET Pharmacokinetic Modeling at the Athinoula A. Martinos Center at MGH. Price is a leader in the study and application of quantitative positron emission tomography (PET) methods. Prior to this, Price worked with Pittsburgh colleagues to lead the first fully quantitative pharmacokinetic evaluations of 11C-labeled Pittsburgh compound-B (PIB), one of the most widely used PET ligands for imaging amyloid beta plaques. As a principal investigator at MGH, Price continues work to validate novel PET methods for imaging biological markers of health and disease in studies of aging and neurodegeneration, including studies of glucose metabolism, protein expression, neurotransmitter system function, and tau and amyloid beta plaque burden.
