GABAA receptor positive allosteric modulator
In
GABA is a major inhibitory neurotransmitter in the central nervous system. Upon binding, it triggers the GABAA receptor to open its chloride channel to allow chloride ions into the neuron, making the cell hyperpolarized and less likely to fire. GABAA PAMs increase the effect of GABA by making the channel open more frequently or for longer periods. However, they have no effect if GABA or another agonist is not present.
Unlike
In
History
The GABAA receptors have historically been a target of drug treatment research. The earliest compounds were ionic compounds, such as bromide.
Barbiturates
In 1903, the first psychoactive derivative of barbituric acid was synthesized and marketed for headaches. Within 30 years, many other barbiturates were developed and found use as sedatives, sleep aids and general anesthetics. Although barbiturates fell out of favor, they continue to serve as a short-acting anesthetic and anti-epileptic drugs.
Benzodiazepines
Benzodiazepines function by binding to the benzodiazepine site on most, but not all, GABAA receptors. GABAA modulation by benzodiazepine site agonists is self-limiting. The channel conductance is not higher in the presence of benzodiazepine and GABA than the conductance with the presence of only high GABA concentrations. Additionally, in the absence of GABA the presence of benzodiazepines alone does not open the chloride channel.[3]
Neurosteroids
Certain metabolites of
Receptor
![](http://upload.wikimedia.org/wikipedia/commons/thumb/0/05/GABAA_receptor_binding_sites.jpg/220px-GABAA_receptor_binding_sites.jpg)
The GABAA receptors are made up of subunits which form a receptor complex. Humans have 19 receptor subunits and are classified into α (1–6), β (1–3), γ (1–3), δ, ε, π, θ, and ρ (1−3). The function of the receptor is different according to how the
Available agents
- Chloral hydrate (and related trichloroethanol prodrugs)
- Barbiturates
- Benzodiazepines
- Nonbenzodiazepines (e.g., zaleplon, zolpidem, zopiclone)
- Inhalational anesthetics (e.g., diethyl ether, halothane, isoflurane)
- Etomidate
- Propofol
- Neurosteroids (e.g., brexanolone, zuranolone, alphaxalone (veterinary))
- Kavalactones
- Ethanol
Applications
Barbiturates
Barbiturates' precise action sites have not yet been defined. The second and third
Insomnia
Barbiturates were introduced as
Anticonvulsant
Sedation
![](http://upload.wikimedia.org/wikipedia/commons/thumb/6/6a/GABA_synapse.jpg/220px-GABA_synapse.jpg)
Benzodiazepine
Synaptic action of benzodiazepines: GABAA receptors located at synapses are activated when they are exposed to high concentration of GABA. Benzodiazepines enhance the receptor affinity for GABA by increasing the decay of spontaneous miniature inhibitory postsynaptic currents (mIPSC).[12][13]
Analgesia
Sedative actions of benzodiazepines limit their usefulness as
Schizophrenia
Benzodiazepines are used as a supporting treatment in patients with schizophrenia.[3]
Depression
A GABAergic hypothesis for depression has been proposed which places the GABA system in a central role in the pathophysiology of depression. Clinical studies have shown that alprazolam and adinazolam have antidepressant activities in patients with major depressive disorder. Unfortunately, it is not known which receptor subtype is responsible for the antidepressant activities.
Studies in y2 knockout mice have shown that they display increased anxiety and depressive-like symptoms in despair-based tests. The mice also had increased corticosterone concentration, which is a symptom in major depression in humans. The y2 subunit is associated with α1-α6 subunits, which are all known α subunits, so these studies do not show which of the α subunits are related to the depressive-like symptoms. Other studies with α2 knockout mice have displayed increased anxiety and depression-like symptoms in conflict-based feeding tests. The fact that anxiety and depression are often linked seems to indicate that the α2 subunit might be a valid target for a GABAA antidepressant.[3]
Stroke
Preclinical studies have shown that benzodiazepines can be effective in reducing the effect of strokes for up to three days after the drug has been administered.[3]
Neurosteroids
Neurosteroids can act as allosteric modulators of neurotransmitter receptors, such as the GABAA,[15][16][17][18] NMDA,[19] and sigma receptors.[20] The neurosteroid progesterone (PROG) that activates progesterone receptors expressed in peripheral and central glial cells.[21][22][23][24] Additionally it has been surmised that the 3α-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone increase the GABA-mediated chloride currents while pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate on the other hand display antagonistic properties at the GABAA receptors.
Synthesis
Barbituric acid
Barbituric acid is the parent compound of barbiturate drugs although barbituric acid itself is not pharmacologically active. Barbiturates were synthesized in 1864 by Adolf von Baeyer by combining urea and malonic acid (Figure 5). A synthesis process was later developed and perfected by French chemist Edouard Grimaux in 1879, making possible the subsequent widespread development of barbiturate derivatives.[25] Malonic acid was later replaced by diethyl malonate, as using the ester avoids the need to deal with the acidity of the carboxylic acid and its unreactive carboxylate (see figure 6). Barbituric acid can form a large variety of barbiturate drugs by using the Knoevenagel condensation reaction.[26]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Synthesis_and_discovery_of_chlordiazepoxide.jpg/390px-Synthesis_and_discovery_of_chlordiazepoxide.jpg)
Benzodiazepines
The structure that the first benzodiazepine is based on was discovered by Leo H. Sternbach. He thought the compound had a heptoxdiazine structure (Figure 7) but it was later determined to be a quinazoline-3-oxide. Possible drug candidates were then synthesized from that compound and screened for activity. One of these compounds was active, chlordiazepoxide. It was marketed in 1960 and became the first benzodiazepine drug.[27]
Biosynthesis of neurosteroids
Structure-activity relationship
Barbiturates
Benzodiazepines
![](http://upload.wikimedia.org/wikipedia/commons/8/82/1%2C4-Benzodiazepin-2-on.png)
According to research performed by Maddalena et al., using
![](http://upload.wikimedia.org/wikipedia/commons/thumb/e/eb/Neurosteroid_R-group_analogs.jpg/220px-Neurosteroid_R-group_analogs.jpg)
Neurosteroids
In the mid 1980s, the
See also
- GABA agonist
- GABA antagonist
- GABA receptor
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Further reading
- Faizi M, Dabirian S, Tajali H, Ahmadi F, Zavareh ER, Shahhosseini S, Tabatabai SA (Feb 2015). "Novel agonists of benzodiazepine receptors: design, synthesis, binding assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone and 3-amino-1,2,4-triazole derivatives". Bioorganic & Medicinal Chemistry. 23 (3): 480–7. PMID 25564376.