作者: Joerger, Andreas C ; Tjaden, Amelie ; Poso, Antti ; Shevchenko, Ekaterina ; Tesch, Roberta ; Lučić, Aleksandar ; Raab, Monika ; Balourdas, Dimitrios-Ilias ; Kronenberger, Thales ; Elson, Lewis ; Strebhardt, Klaus ; Sanhaji, Mourad ; Zhubi, Rezart ; Berger, Lena M ; Knapp, Stefan ; Krämer, Andreas ; Rak, Marcel ; Hanke, Thomas

Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicity in vivo, which complicates the use of MRIA9 as a tool compound. Here, we present a structure-based approach involving the back-pocket and gatekeeper residues, for narrowing the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one-based inhibitors towards SIK kinases, eliminating PAK activity. Optimization was guided by high-resolution crystal structure analysis and computational methods, resulting in a pan-SIK inhibitor, MR22, which no longer exhibited activity on STE group kinases and displayed excellent selectivity in a representative kinase panel. MR22-dependent SIK inhibition led to centrosome dissociation and subsequent cell-cycle arrest in ovarian cancer cells, as observed with MRIA9, conclusively linking these phenotypic effects to SIK inhibition. Taken together, MR22 represents a valuable tool compound for studying SIK kinase function in cells.

2011-05-10·Journal of Alzheimer's Disease3区 · 医学

Anti-Amnesic and Neuroprotective Actions of the Sigma-1 Receptor Agonist (-)-MR22 in Rats with Selective Cholinergic Lesion and Amyloid Infusion

3区 · 医学

Article

作者: Prezzavento, Orazio ; Leanza, Giampiero ; Antonini, Vuokko ; Marrazzo, Agostino ; Ronsisvalle, Giuseppe ; Ronsisvalle, Simone ; Kleiner, Giulio ; Coradazzi, Marino

Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study,we have investigated the anti-amnesic and neuroprotective actions of the compound (-)-methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate) [(-)-MR22],a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the basal forebrain and the hippocampus, respectively. At about five–six weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss oramyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-)-MR22 normalized the levels of cell-associated amyloid-β protein precursor (AβPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AβPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection.

2006-04-01·European Journal of Pharmacology3区 · 医学

A novel adamantane derivative attenuates retinal ischemia–reperfusion damage in the rat retina through σ1 receptors

3区 · 医学

Article

作者: Ronsisvalle, Giuseppe ; Bucolo, Claudio ; Caputi, Achille ; Drago, Filippo ; Marrazzo, Agostino ; Mazzon, Emanuela ; Ronsisvalle, Simone ; Cuzzocrea, Salvatore

The effects of a novel N-methyladamantan-1-amine derivative [(-)-MR22] with high sigma1 receptor affinity were investigated on retinal degeneration using a rat model of ischemia-reperfusion injury. The animals were anaesthetized and retinal ischemia was induced by elevating the intraocular pressure to 120 mm Hg for 45 min. The drug was injected intraperitoneally before the ischemic damage. Retinal biochemical changes, i.e. increase of lactate content and decrease of glucose and ATP were significantly inhibited by the new and selective sigma1 receptor ligand compared to the ischemic control group. The effect of (-)-MR22 was antagonized by pre-treatment with the sigma1 site antagonist. The protective effect of (-)-MR22 on ischemic retina was confirmed by the histological analysis. These findings suggest that (-)-MR22 serves as a retinal neuroprotective agent and acts as a sigma1 receptor agonist.

100 项与 MR-022 相关的药物交易

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