L-838,417
Encyclopedia
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.
L-838,417 is a subtype-selective GABAA
agonist, acting as a partial agonist
at α2
, α3
and α5
subtypes, but as an antagonist
at the α1
subtype, and has little affinity for the α4
or α6
subtypes. This gives it selective anxiolytic
effects, which are mediated mainly by α2 and α3 subtypes, but with little sedative
or amnestic effects as these effects are mediated by α1. Some sedation might still be expected due to its activity at the α5 subtype, which can also cause sedation, however no sedative effects were seen in animal studies even at high doses, suggesting that L-838,417 is primarily acting at α2 and α3 subtypes with the α5 subtype of lesser importance.
As might be predicted from its binding profile, L-838,417 substitutes for the anxiolytic benzodiazepine chlordiazepoxide
in animals, but not for the hypnotic
imidazopyridine
drug zolpidem
.
The synthesis of L-838,417 and similar compounds was described in 2005 in the Journal of Medicinal Chemistry
.
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
drug used in scientific research. It has similar effects to benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugs, but is structurally distinct and so is classed as a nonbenzodiazepine
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
anxiolytic. The compound was developed by Merck, Sharp and Dohme.
L-838,417 is a subtype-selective GABAA
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
agonist, acting as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
at α2
GABRA2
Gamma-aminobutyric acid receptor subunit alpha-2 is a protein that in humans is encoded by the GABRA2 gene....
, α3
GABRA3
Gamma-aminobutyric acid receptor subunit alpha-3 is a protein that in humans is encoded by the GABRA3 gene.- Function :GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gated chloride channels...
and α5
GABRA5
Gamma-aminobutyric acid A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the GABRA5 gene.-Function:...
subtypes, but as an antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
at the α1
GABRA1
Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
subtype, and has little affinity for the α4
GABRA4
Gamma-aminobutyric acid receptor subunit alpha-4 is a protein that in humans is encoded by the GABRA4 gene....
or α6
GABRA6
Gamma-aminobutyric acid receptor subunit alpha-6 is a protein that in humans is encoded by the GABRA6 gene.One study has found a genetic variant in the gene to be associated with the personality trait neuroticism....
subtypes. This gives it selective anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
effects, which are mediated mainly by α2 and α3 subtypes, but with little sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
or amnestic effects as these effects are mediated by α1. Some sedation might still be expected due to its activity at the α5 subtype, which can also cause sedation, however no sedative effects were seen in animal studies even at high doses, suggesting that L-838,417 is primarily acting at α2 and α3 subtypes with the α5 subtype of lesser importance.
As might be predicted from its binding profile, L-838,417 substitutes for the anxiolytic benzodiazepine chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
in animals, but not for the hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
imidazopyridine
Imidazopyridine
The imidazopyridines are a class of drugs defined by their chemical structure. They are generally GABAA receptor agonists, however recently proton pump inhibitors in this class have been developed as well. Despite usually being similar to them in effect, they are not chemically related to...
drug zolpidem
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
.
The synthesis of L-838,417 and similar compounds was described in 2005 in the Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
The Journal of Medicinal Chemistry , is a peer-reviewed scientific journal, published since 1959 by the American Chemical Society...
.