June 23, 2021

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Progress in drug development of targeting GABA receptors

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Progress in drug development of targeting GABA receptors

Progress in drug development of targeting GABA receptors


Progress in drug development of targeting GABA receptors.  Gamma-aminobutyric acid (γ-aminobutyric acid, GABA) is formed by removing the carboxyl group at the α position from the precursor glutamate through the action of glutamate decarboxylase.  It is an important inhibitory neurotransmitter, with about 50% of the The central synapse uses GABA as a transmitter and regulates body functions.

Progress in drug development of targeting GABA receptors

Studies have found that the decrease in the level of GABA in the brain is related to the occurrence of mental and psychological disorders such as anxiety, depression, epilepsy, Parkinson, or central nervous system diseases [1].

GABA receptors have three subtypes, namely GABAA receptors, GABAB receptors and GABAC receptors. GABAB receptors are metabotropic receptors, and GABAA receptors and GABAC receptors are ionotropic receptors, which play a key role in the central nervous system and peripheral tissues.


GABAA receptor is a pentagonal heterogeneous polypeptide oligomer composed of 5 subunits embedded in the double lipid plasma membrane of nerve cells. It belongs to the ligand-gated channel superfamily and is resistant to the spasm agent bicuculline ( Bic) and other GABA receptor antagonists are sensitive, and are widely distributed in animals, and are distributed throughout the nervous system and peripheral tissues. GABA activates the chloride ion channel through the GABAA receptor on the neuron cell membrane, which leads to the influx of chloride ion in the cell, produces inhibitory postsynaptic potentials, and inhibits neuronal excitement.


GABAB receptors are more sensitive to bacteramic acid (Bac) and exist in the pre-synaptic and post-synaptic parts of neurons. They are distributed in the neocortex and hippocampus of mammals. They are found in the substantia nigra, globus pallidus, The density of GABAB receptor binding sites in the lateral amygdala is higher. GABAB receptors can be divided into 22 subunits of GABAB1 and GABAB. GABAB receptors increase potassium ion conductance in the postsynaptic membrane and produce inhibitory postsynaptic potentials. In the presynaptic membrane, calcium ion conduction produces presynaptic inhibition. Therefore, GABAB receptors mediate “slowly” through the entire central nervous system. “Inhibit neurotransmission and affect the excitability of neurons and the release of inhibitory transmitters.


GABAC receptor is a pentameric protein complex composed of 5 subunits. It has pharmacological properties such as insensitivity to Bic and Bac. It is a new type of chloride ion permeable ion migration GABA receptor. It is not only found in the retina, but also distributed in the spinal cord, thalamus, pituitary gland and intestines of mammals, and participates in functions such as vision, memory, and sleep.


There are two production pathways of GABA in organisms, namely GABA branch pathway and polyamine degradation pathway. Among them, GABA branches are widely present in animals, plants and microorganisms, and are the main way to produce GABA in organisms. This branch is a branch of the tricarboxylic acid cycle. The α-ketoglutarate in the tricarboxylic acid cycle produces L-glutamic acid (L-Glu) through transamination. L-Glu is in the glutamate decarboxylase Under the action of decarboxylation, GABA is generated. After exerting its biological function, it can be transaminated by GABA transaminase, and then oxidized to succinic acid, and then enter the tricarboxylic acid cycle. However, when plant tissues are stimulated by the adversity environment, GABA produced by the GABA branch is insufficient, and the polyamine degradation pathway appears in plants as an auxiliary pathway for GABA production. In this way, putrescine and polyamine in plant cells undergo deamination and dehydrogenation to generate GABA under the action of diamine oxidase or polyamine oxidase.


GABA branch and polyamine degradation pathway


1. Research progress of GABA receptor modulators

According to incomplete statistics, according to the cortellis database, the statistics of GABA receptor modulators at the clinical stage and above are as follows:

1) Research status: Among them, 21 are listed, 16 are registered/pre-registered, 7 are phase 3 clinical, 27 are phase 2 clinical, and 22 are phase 1 clinical.

2) Distribution of subtypes: Among them, 34 are GABAA receptor modulators, 12 are GABAB receptor modulators, and GABAc receptor modulators have not yet entered the clinical stage; 23 GABA modulators have unclear receptors.

3) Indications: The top rankings include epilepsy (32), insomnia (20), anxiety (11), neuropathic pain (10), Lennox-Gastaut syndrome (7), narcolepsy (7), alcoholism (6), migraine (6), neuralgia after herpes zoster (6), severe depression (5), panic disorder (5), Parkinson (5).

4) The detailed information of GABA receptor modulators that will be on the market are as follows:



2. Introduction of key drugs

1) Drugs that act on GABAA receptors

(1) Benzodiazepine GABAA receptor agonist

GABAA receptor is the most abundant GABA receptor in mammalian brain. It has at least five binding sites. It is a complex composed of three parts: GABA recognition site, benzodiazepine recognition site and chloride channel. Benzodiazepines are currently the most important class of drugs that act on GABAA receptors in clinical practice. They are mainly used for anti-anxiety, anti-epileptic, anti-convulsant, muscle relaxant and sedative hypnosis. Clobazam is a kind of benzodiazepine derivative, which is widely used in the treatment of various epilepsy around the world. The commonly used benzodiazepines in China are clonazepam and nitrazepam. Pan has a longer action time and has a stronger anticonvulsant effect than nitrazepam, so it is more widely used. Clonazepam is approved for the adjuvant treatment of panic disorder and various types of epileptic seizures: a single agent or a single agent for syndromes including Lennox-Gastaut syndrome (LGS), infantile spasms, Dravet syndrome, juvenile myoclonic epilepsy, etc. Adjuvant therapy; at the same time, clonazepam has a certain therapeutic effect on comorbid epilepsy, such as sleep disorders, mood disorders, anxiety, migraine, autism spectrum disorders, dementia, etc.

(2) Non-benzodiazepine GABAA receptor agonists

Benzodiazepines, as common sedative and hypnotic drugs, have been less used to treat insomnia due to their residual effects, respiratory depression, drug resistance, and addiction. Non-benzodiazepine hypnotic drugs have become the first choice for the treatment of insomnia. Such drugs do not affect the normal sleep physiological structure of healthy people, and can even correct the sleep disorder structure of insomnia patients, and there is no residual effect in the next morning, and it is not easy to develop drug resistance. Sex and drug addiction, non-rebound insomnia. At present, the non-benzodiazepine drugs commonly used in clinical practice in China include Zolpidem, eszopiclone, and zaleplon, which inhibit the nervous system by increasing the conduction of chloride ions, and produce a sedative effect. Its selectivity is stronger, The effect is better, and there are fewer adverse reactions.

2) Drugs that act on GABAB receptors

Disorders of GABAB receptor function can lead to the pathogenesis of a variety of neurological diseases. The close connection between drug addiction, epilepsy and pain and GABAB receptors has long been recognized [3]. Baclofen is the first GABAB receptor agonist to be used clinically. It has anesthesia, antispasmodic and antiepileptic effects, but it has side effects such as mediating cognitive impairment. UCB’s Xyrem (sodium oxybate) is used for the treatment of narcolepsy and cataplexy in adolescents and children under 7 years of age. Its unique cationic composition can reduce sodium in patients with narcolepsy after long-term medication Risk of excessive ion intake.

3) Drugs that act on GABAc receptors

At present, no drugs acting on the GABAc receptor have entered the clinical stage. The selective GABAc receptor agonist, namely partially folded cis-aminocrotonic acid, has been confirmed to be expressed in the retina of mammals; selective GABAc receptor The antagonist 4-(1,2,5,6-tetrahydropyridine)-methyl hypophosphorous acid (TPMPA) has shown important biological activities, including: (1) improving the memory function of mice and chicks; (2) impact Sleep-wake behavior of mice; (3) inhibit ammonia-induced apoptosis in hippocampal neurons; (4) regulate the release of hormones from the pituitary gland.



GABA, as the resident amino acid of living organisms, has been affecting us extensively and profoundly. As a key intermediate in the organism’s stress response and an important signal transmitter in the organism, it presents an orderly process from simple to complex from lower to higher organisms.

As an important signaling molecule in plants and the human body, it plays a role in linking the past and the next. Especially for the receptor regulation mechanism in higher organisms, it is an important factor in the pathogenesis and treatment of a variety of pathologies. With the advancement of science and technology,

GABA as a medium can help understand more stress and the physiological regulation process of nerves, and use GABA more rationally and accurately [4].



(source:internet, reference only)

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