AMPK is considered as a potential high value target for metabolic disorders. Here, we present the molecular modeling, in vitro and in vivo characterization of Activator-3, 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid, an AMP mimetic and a potent pan-AMPK activator. Activator-3 and AMP likely share common activation mode for AMPK activation. Activator-3 enhanced AMPK phosphorylation by upstream kinase LKB1 and protected AMPK complex against dephosphorylation by PP2C. Molecular modeling analyses followed by in vitro mutant AMPK enzyme assays demonstrate that Activator-3 interacts with R70 and R152 of the CBS1 domain on AMPK γ subunit near AMP binding site. Activator-3 and C2, a recently described AMPK mimetic, bind differently in the γ subunit of AMPK. Activator-3 unlike C2 does not show cooperativity of AMPK activity in the presence of physiological concentration of ATP (2 mM). Activator-3 displays good pharmacokinetic profile in rat blood plasma with minimal brain penetration property. Oral treatment of High Sucrose Diet (HSD) fed diabetic rats with 10 mg/kg dose of Activator-3 once in a day for 30 days significantly enhanced glucose utilization, improved lipid profiles and reduced body weight, demonstrating that Activator-3 is a potent AMPK activator that can alleviate the negative metabolic impact of high sucrose diet in rat model.

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Dopaminergic signalling is crucial for a variety of brain functions, and abnormal dopamine regulation leads to neuropsychiatric disorders. Dopamine (DA) receptors are members of the G protein-coupled receptors (GPCRs) superfamily, with seven transmembrane spanning domains. DA, upon release from pre-synaptic neurons, activates dopamine receptor subtypes D1 to D5 and induces Gαs/olf-and Gαi/o-mediated intracellular signalling. Defects in DA signalling cause either over-activation or dysfunction of DA regulation, leading to major psychiatric and neurological disorders, including Parkinson's, schizophrenia, attention deficit with hyperactivity disorder, and bipolar disorder. Molecules that act as antagonists/agonists on D2/D3 receptors have been used clinically to treat many neuropsychiatric and neurodegenerative disorders. Most of the anti-psychotic drugs in use are primarily based on D2 receptor antagonism and serotonin receptor antagonism. However, antipsychotic drugs were developed 50 years ago, and the efficacy of these drugs has not been refined/upgraded very much. Thus, there is a great need to develop novel therapeutic strategies in designing/discovering a newer class of drugs. This can be achieved by having a better understanding about DA regulation and dopaminergic signalling in neuropsychiatric disorders. The in silico approach can be a tool for studying DA receptors and other protein targets involved in dopaminergic signalling. Utilising the existing knowledge on DA signalling in combination with various in silico approaches can be helpful in designing new chemical entities (NCEs). This review focuses on receptor functioning and dopaminergic signalling in major neuropsychological disorder, current therapeutic strategies, and future perspectives.