**1. Introduction**

The ground breaking discovery of Gamma-aminobutyric acid (GABA) played an astonishing role in neural control theory in 1950's. In the human cortex GABA is the primary inhibitory neurotransmitter [1]. In the initial developmental stage of life, GABA functions as an excitatory element which influences many physiological processes like neuronal proliferation, neurogenesis, migration, differentiation and preliminary circuit building. After maturation of CNS, GABA acts as an inhibitory neurotransmitter which is controlled as chloride or cation transporter expression. GABA also plays a vital role in interstitial neurons development of white matter along with oligodendrocyte development. Whereas the basic fundamental cellular mechanisms are not well described though it is proven that a lot of neurological diseases are well involved through GABA dependant pathway which includes white matter abnormalities, including anoxic-ischemic injury, anxiety, insomnia and schizophrenia [2]. GABA receptors are majorly classified into two main types ionotropic GABAA and

GABAC receptors and the metabotropic GABAB receptor. GABAA acts by activating the fast-hyperpolarizing negative ion channel (Cl− ) and diffuse by the means of concentration gradient to hyperpolarize post synaptic mature neurons [3, 4]. Whereas another kind of ionotropic receptor was discovered GABAC with 3ρ subunits [5]. GABAB receptors consist of two subunits, GABAB1and GABAB2 which are responsible for slower inhibitory transmission. These receptor activations are coupled with K+ /Ca+ channels through G-protein mediated secondary pathway [6].

Natural molecules with a wide range of chemical structures have been shown to have GABAA receptor modulating potential due to the structural heterogeneity of and more than one number of binding sites. It has different pharmacological effects depending on the mechanism of action, the binding site and the affinity of the compounds. These effects have been investigated using different *in vitro* and *in vivo* models [7–9].

The versatile binding nature of benzodiazepine binding site of GABA receptor allows multiple molecules to bind and modulate the functions of GABA in a very specific manner. So, this class of compounds are used for the treatment of anxiety, convulsion, insomnia by non-specifically modulating all five α subunits. This non selective nature of these compounds generates unwanted side effects like tolerance and dependence. Therefore, there is an immediate need for finding safe drugs, with increased anxiolytic and decreased sedative potential. In recent decades, various reports have been made on natural products with GABAergic activity and, different various methods have been used to describe the effects. Hence, this review aimed to collect the existing data and make the obtained results as comparable as possible, thus facilitating the discussion of structure–activity relationships [10].

#### **1.1 Synthesis**

GABA is mainly produced from α-decarboxylation of glutamate by the enzyme glutamic acid decarboxylase (GAD) and metabolized by the actions of GABAtransaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) into succinate respectively. Through the use of the pyridoxal-5′-phosphate-dependent interconversion steady state concentration of GABA is achieved in-vivo (apo-GAD). At least 50 percent of the total GAD present in the brain is apo-GAD [10]. Inorganic phosphate promotes the activation of GAD and blocked by aspartate, GABA and ATP. The ATP facilitates and stabilizes apo-GAD formation which further stimulates the development of GABA. At 37°c temperature apo-GAD has a half-life of few minutes without ATP. GAD mainly consists of two isoforms of distinct molecular weights (65 and 67 kD) which are the products of chromosomes 2 and 10 in humans.

After synthesis, GABA vesicular release has specific mechanisms. GABA is assembled using Mg2 + activated ATPase into vesicles. This method is energy-dependent and requires adenosine triphosphate and magnesium. Calcium-dependent GABA vesicular release appears to result in a temporary increase in the synaptic cleft's GABA concentration and the binding of the receptor to evoke action. Through the sodium and chloride reuptake mechanism of the GABA transporter (GAT) to the presynaptic neuron and surrounding glia, quick synapse removal takes place. GABA is then reused into metabolites that are eventually used for GABA resynthesis by breakdown. GABA-oxoglutarate transaminase, succinic semialdehyde dehydrogenase and glutamate decarboxylase (GAD) are three enzymes required for GABA metabolism and resynthesis. The deterioration of GABA to succine semi-aldehyde is catalyzed by the enzyme GABA oxoglutarate transaminase. The latter is then oxidized by means of succinic semialdehyde dehydrogenase into succinic acid. Ligands associated with these GABA procedures will regulate the action of GABA [11].
