GSK-3/3, Glycogen Synthase Kinase

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

A crucial kinase that functions as an intermediary in numerous intracellular signaling pathways is the enzyme glycogen synthase kinase-3 (GSK-3) 898... 

Martinez A, Castro A, Dorronsoro I, et al. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev 2002, 22 373-84. 

Lithium Mechanism of action uncertain suppresses inositol signaling and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase No significant antagonistic actions on autonomic nervous system receptors or specific CNS receptors no sedative effects Bipolar affective disorder-prophylactic use can prevent mood swings between mania and depression Oral absorption, renal elimination half-life 20 h. narrow therapeutic window (monitor blood levels) Toxicity Tremor, edema, hypothyroidism, renal dysfunction, dysrhythmias pregnancy category D Interactions Clearance decreased by thiazides and some NSAIDs... 

Actually, lithium has been associated with many effects that are believed to be neuroprotective (234). Most importantly, it reduces the activity of glycogen synthase kinase-3 (GSK-3), which leads to reduced production of the tau protein (235,236). However, lithium may actually increase the production of amyloid beta (237), although previous reports have suggested that lithium reduces amyloid beta and its consequent toxicity (238,239). 

Noh MY, Chun K, Kang BY, Kim H, Park JS, Lee HC et al (2013) Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer s disease. Biochem Biophys Res Commun 435 274-281... 

Abstract Glycogen synthase kinase 3 (GSK-3) has emerged as a prominent therapeutic target for intervention in several diseases including non-insulin-dependent diabetes mel-litus, Alzheimer s disease, stroke, bipolar disorder and affective disorders. In the present review we briefly summarise the properties of GSK-3, focusing primarily on the role of GSK-3 in Alzheimer s disease. Furthermore, we discuss the potential for therapeutic benefit of GSK-3 inhibitors. 

Bhat RV, Budd Haeberlein SL, Lindquist JM (2006) Inhibition of GSK-3 as therapeutic strategy in disease efficacy of AR-A014418. In Marlines A, Castro A, Medina M (eds) Glycogen synthase kinase 3 (GSK-3) and its inhibitors. Wiley, New Jersey, p 243... 

Glycogen synthase kinase-3 (GSK-3 sites C30, C34, C38 and C42 also phosphorylates inhibitor-2 (see below), thereby activating protein phosphatase-1). 

Lithium is thought to act by blocking the fnnction of an enzyme called glycogen synthase kinase-3 (GSK-3(3) in the brain. Among other snbstances fonnd to block GSK-3p elsewhere in the body, lithinm salts are the only capable to get into the brain and then to combat bipolar disorder. Alan Kozikowski (University of Ilhnois in Chicago) took a directed, rational approach showing that newly discovered compounds called (3-(benzofnran-3-yl)-4-indol-3-yl) maleimides) are potent and relatively selective GSK-3 3 inhibitors. ... 

Figure 3 Phosphorylation of glycogen synthase by glycogen synthase kinase 3 (GSK-3). (a) In vitro, phosphorylation occurs first at site 5 by casein kinase II. Then GSK-3 phosphorylates in sequence site 4, then 3c, 3b, and last, 3a. (b) Phosphorylation of sites 3a and 3b by different protein kinases, PK and PKy. In vivo, these kinases can phosphorylate sites 3a and 3b independent of prior phosphorylation of sites 3c, 4, and 5. PAS kinase has been shown to phosphorylate site 3a (S640). ...

Mild TBI increases the phosphorylation of inhibitory site serine of glycogen synthase kinase-3 (GSK-3()), which coincides with increased serine" phosphorylation of its upstream kinase (PKB) and accumulation of its downstream target P-catenin in the hippocampus (Shapira et al., 2007). Mild TBI also mediates a depressive behavior which is evident as early as 24 h post-injury. Pretreatment with GSK-3 inhibitors, lithium, or L803-mts retards mild TBI-induced depression. It is suggested that mild TBI elicits a prosurvival cascade of PKB/GSK-3 / -catenin as part of a rehabilitation program (Shapira et al., 2007). 

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