• ADaM
• ADaM AMPK
• AMPK
• AMPK activators
• AMPK Modulators
• attivatori
• attivatori AMPK

AMP-activated protein kinase (AMPK) is a master sensor of metabolic stress and exists as heterotrimeric αβγ complexes. It is an energy sensor that plays a key role in maintaining the energy landscape of cells. AMPK exist as heterotrimeric kinase, composed by a catalytic α subunit and a regulatory β and γ subunit.The α subunit is composed of a serine/threonine which form the kinase domain, an autoinhibitory domain, a α-hook domain, a C-terminal β subunit-binding domain. The β subunit is composed by glycogen binding domain and a C-terminal domain that binds the α and γ subunits and a N-terminus which can be
myristoylated which is probably a mechanism to facilitate the shuttling of AMPK in the nucleus. The γ subunit has a β subunit-binding region and two bateman domains that are assembled in a head-to-head manner. Each bateman domain are composed of two tandem CBS motifs. There are four CBS motifs present in the γ subunit, the CBS1 and 3 can exchangeably bind AMP, ADP, ATP but CBS1 have a higher affinity for all three nucleotides. The CBS4 permanently binds a nonexchangeable AMP molecule, finally the CBS2 is empty because of its lacking of the aspartate residue, required to make the hydrogen bond with the hydroxyl group of the pentose sugar in the adenine nucleotides. The most well defined mechanism for
AMPK activation is the phosphorylation at Thr 172 of the α-subunit, which is regulated by at least three kinase and three phosphatases, the kinase (LKB1, CaMKK2 and TAK1) and three phosphatase (PP2A, PP2C and PPM1E). In the energy-replete condition there are a low AMP/ATP and ADP/ATP ratios, indeed the phosphatases can easily access to the T172 keeping it in the unphosphorylated and inactive state; when the energy in the cell goes down those ratios rise up and ADP and AMP can bind the CBS domains in the γ-subunit determinating a structural change in the AMPK conformation, and preventing the phosphatases from accessing T172 thus increasing its phosphorylation. In addition the binding of AMP and ADP (to lesser extent) to the CBS3 unit stimulates the T172 LKB1-mediated phosphorylation which requires the myristoylation on the amino terminal part of the AMPK β- subunit, finally the binding of AMP but not ADP, to CBS1 increase the intrinsic AMPK activity by inducing allosteric activation. AMPK as an energy sensor that plays a key role in whole-body energy homeostasis has a lot of physiological functions. The first known function of AMPK is the regulation of lipid metabolism, indeed AMPK inhibits the novo synthesis of fatty acids (FAs), cholesterol and triglycerides (TGs) and activates the FAs uptake and fatty acid oxidation (FAO). Moreover AMPK can also increase the glucose metabolism by inducing the translocation of GLUT 1 receptors on the plasma membrane and the inhibition of glycogen synthase. AMPK can inhibit protein synthesis by blocking the cap-dependent translation during both initiation and elongation steps. AMPK also induce an inhibitory phosphorylation of transcription initiation factor 1A this action downregulates the ribosomal RNA synthesis. Due to the various physiological functions of AMPK, it also has a crucial role in various type of diseases especially in type II diabetes, inflammation and cancer. The regulation of AMPK is of great interest in the study of Type II diabetes and metabolic syndrome, due to accumulating evidence suggesting that the dysregulation of AMPK plays an important role in the development of insulin resistance and type II diabetes, and that AMPK activation (either physiological or pharmacological) can prevent and/or ameliorate some of the pathologies of insuline resistance and type II diabetes. Furthermore AMPK have a crucial role in cancer, it can be compared to a double-edged sword because it plays a different role in cancer genesis and in cancer development, for these reason a suitable activation or inhibition of AMPK maybe can bring benefits for this type of disease. Finally it has been shown that AMPK possess high anti-inflammatory properties, so it may be proposed as a possible target for new anti-inflammatory drug. (1) (2). During my thesis work we did a docking study using the AMPK structure crystallized with A-769662, an allosteric activator who acts by preventing dephoshprylation of Thr 172 by binding AMPK in a cleft between the kinase α-domain and the carbohydrate-binding domain of the β-subunit (3). Therefore using the results from the docking study, we hypothesized new possible activators bearing phthalimide as central core structure. We maintained the nitrile group by attaching it to the imide nitrogen atom on the phthalimide, and we decorated the molecule on position 4 of the phtalimide core with different suitable arylamide substituents which bring flexibility to the molecule and more chances of doing additional hydrogen bond in the binding site.