Gabaculine is a naturally occurring

neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...

first isolated from the bacteria ''

Streptomyces ''Streptomyces'', from στρεπτός (''streptós''), meaning "twisted", and μύκης (''múkés''), meaning "fungus", is the largest genus of Actinomycetota, and the type genus of the family Streptomycetaceae. Over 700 species of ''St ...

toyacaensis'', which acts as a potent and irreversible

GABA transaminase In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalysis, catalyzes the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons suc ...

inhibitor, and also a

GABA reuptake inhibitor A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to incr ...

. Gabaculine is also known as 3-amino-2,3-dihydrobenzoic acid hydrochloride and 5-amino cyclohexa-1,3 dienyl carboxylic acid. Gabaculine increased

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

levels in the brain and had an effect on convulsivity in mice.

Mechanism of action

Gabaculine includes a comparable structure to

and a dihydrobenzene ring. This comparable GABA structure is used in order to be able to take the place of GABA during the first steps of transamination, including transaldimination and 1,3-prototrophic shift to the pyridoxamine imine. Following this, a proton from the dihydrobenzene ring is abstracted by an enzymatic base, thus causing the ring to become aromatic. The aromatic stabilization energy of the aromatic ring is what causes this reaction to be irreversible, thus causing the complex not to react further.

Preclinical studies

Animal studies to determine the effect of gabaculine on GABA levels in the brain were heavily conducted around the 1970s. These in vivo studies involved mostly the use of mice that underwent intravenous administration of this drug. Each of these studies concluded that gabaculine has a great potential to increase the GABA levels in the brain of these mice in a time dependent manner. Along with determining the effect of GABA levels, in vivo studies were conducted to investigate the ability of gabaculine to inhibit convulsions in mice. Results indicated that gabaculine provided a clear anticonvulsant effect against seizures induced by high doses of chemoconvulsants or electroshock. The toxicity of this compound was also investigated using animal mouse models. This study showed that at anticonvulsant doses, gabaculine is extremely potent and toxic when compared to other GABA transaminase inhibitors, with an ED₅₀ of 35 mg/kg and of 86 mg/kg. Because of this potential lethal effect, gabaculine was proved to be too toxic for use as a drug however, it can still be used as a compound to alter GABA levels in studies of experimental

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

Regulation

Gabaculine has not been approved by the FDA as a pharmaceutical entity; however, it can be used as a chemical compound for research purposes only. This compound is not considered a hazardous substance according to OSHA 29 CFR 1910.1200.

References

{{GABA metabolism and transport modulators Amino acids Gamma-Amino acids Neurotoxins GABA transaminase inhibitors GABA reuptake inhibitors GABA analogues