SL-651,498
Encyclopedia
SL-651,498 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.
SL-651,498 is a subtype-selective GABAA
agonist, which acts as a full agonist at α2
and α3
subtypes, and as a partial agonist
at α1
and α5
(although its action at α5 subtypes is much weaker than at the others). In animal studies, it has primarily anxiolytic
effects, although some sedation
, ataxia
and muscle relaxant
effects are observed at higher doses. It substitutes fully for the anxiolytic benzodiazepine chlordiazepoxide
, but only partially substituted for the imidazopyridine
hypnotic drug zolpidem
and the benzodiazepine hypnotic
triazolam
. When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α5 subtype.
SL-651,498 has been suggested for development as a novel non-sedating anxiolytic drug for humans, although it is still only at an early stage of research. Preliminary human trials suggest similar efficacy to lorazepam
as an anxiolytic, but with little or no sedation or impairment of memory, motor skills or cognitive function.
There are other possibly anxioselective compounds in development, such as L-838,417
, NGD 91-3.
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
and anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
drug used in scientific research, with a chemical structure most closely related to β-carboline
Beta-carboline
β-Carboline is an organic amine that is the prototype of a class of compounds known as β-carbolines.-Pharmacology:...
derivatives such as abecarnil
Abecarnil
Abecarnil is an anxiolytic drug from the β-Carboline family. It is one of a relatively recently developed class of medicines known as the nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures...
and gedocarnil
Gedocarnil
Gedocarnil is an anxiolytic....
. 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.
SL-651,498 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, which acts as 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....
and 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...
subtypes, and 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 α1
GABRA1
Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
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:...
(although its action at α5 subtypes is much weaker than at the others). In animal studies, it has primarily anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
effects, although some sedation
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
effects are observed at higher doses. It substitutes fully 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...
, but only partially substituted for the 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...
hypnotic 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...
and the benzodiazepine 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...
triazolam
Triazolam
Triazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
. When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α5 subtype.
SL-651,498 has been suggested for development as a novel non-sedating anxiolytic drug for humans, although it is still only at an early stage of research. Preliminary human trials suggest similar efficacy to lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
as an anxiolytic, but with little or no sedation or impairment of memory, motor skills or cognitive function.
There are other possibly anxioselective compounds in development, such as L-838,417
L-838,417
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...
, NGD 91-3.