An imidazopyridine is a nitrogen containing heterocycle that is also a class of drugs that contain this same chemical substructure. In general, they are GABAA receptor agonists, however recently proton pump inhibitors, aromatase inhibitors, NSAIDs and other classes of drugs in this class have been developed as well. Despite usually being similar to them in effect, they are not chemically related to benzodiazepines. As such, GABAA-agonizing imidazopyridines, pyrazolopyrimidines, and cyclopyrrones are sometimes grouped together and referred to as "nonbenzodiazepines." Imidazopyridines include:
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 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. For instance, under physiological conditions Cl− will flow inside the cell if the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions if the receptor is activated. 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).
Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties.
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.
Etifoxine is an anxiolytic and anticonvulsant drug developed by Hoechst in the 1960s. It is sold in approximately 40 countries for anxiety disorders, without the sedation and ataxia associated with benzodiazepine drugs. It has similar anxiolytic effects to benzodiazepine drugs, but is structurally distinct, although it has structural elements in common with them. Studies suggest is as effective as lorazepam as an anxiolytic, but has fewer side effects. Etifoxine is not approved by the U.S. Food and Drug Administration or the European Medicines Agency. The European Medicines Agency started a review procedure regarding the effectiveness and safety of Etifoxine following a French study that compares Etifoxine's effectiveness to placebo.
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.
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.
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.
CL-218,872 is a sedative and hypnotic drug used in scientific research. It has similar effects to sedative-hypnotic benzodiazepine drugs such as triazolam, but is structurally distinct and so is classed as a nonbenzodiazepine hypnotic.
Y-23684 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.
CGS-20625 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. It produces anxiolytic and anticonvulsant effects, but with no sedative effects even at high doses, and no significant muscle relaxant effects. It is orally active in humans, but with relatively low bioavailability.
Tracazolate (ICI-136,753) is an anxiolytic drug which is used in scientific research. It is a pyrazolopyridine derivative, most closely related to pyrazolopyrimidine drugs such as zaleplon, and is one of a structurally diverse group of drugs known as the nonbenzodiazepines which act at the same receptor targets as benzodiazepines but have distinct chemical structures.
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.
NS-2710 (LS-193,970) is an anxiolytic drug with a novel chemical structure, developed by the small pharmaceutical company NeuroSearch. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. NS-2710 is a potent but non-selective partial agonist at GABAA receptors, although with little efficacy at the α1 subtype and more at α2 and α3. It has anxiolytic effects comparable to chlordiazepoxide, and while it is a less potent anticonvulsant than the related drug NS-2664, it has a much longer duration of action, and similarly to other α2/α3-preferring partial agonists produces little sedative effects or physical dependence.
TP-13 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 subtype-selective partial agonist at GABAA receptors, binding selectively to GABAA receptor complexes bearing α2 and α3 subunits. It has modest anticonvulsant activity although less than that of diazepam, and its main effect is likely to be selective anxiolytic action, as seen with other related α2/3-preferring agonists such as L-838,417.
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.
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.
Imepitoin (INN), sold under the brand name Pexion, is an anticonvulsant which is used in veterinary medicine in Europe to treat epilepsy in dogs. It was recently approved in the United States. The drug also has anxiolytic effects. It was originally developed to treat epilepsy in humans, but clinical trials were terminated upon findings of unfavorable metabolic differences in smokers and non-smokers.
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