Discovery of neuroprotective soluble guanylate cyclase modulators (GCMs) aciting via NO/GC/cGMP/CREB pathway

摘要: NO/cGMP signaling is essential for normal brain function, including learning and memory, mediation of long-term potentiation (LTP). coupled to cholinergic, glutamatergic, dopaminergic systems plays key roles in motor function associated with Parkinson’s disease pathogenesis L-DOPA therapy. In Alzheimer’s Disease (AD), early synaptic failure, has been linked dysfunction gene expression programs mediated via the transcription factor cAMP-response element binding protein (CREB), activation which tightly regulated by NO/cGMP. Since several neurodegenerative disorders continue be dogmatically chemical toxicity NO, soluble guanylyl cyclase (sGC) represents a potential therapeutic approach both AD PD; whereas negative modulation sGC may use some stages PD. Such small molecule modulators (GCMs) can assayed cell cultures measuring levels phosphorylated CREB (pCREB). GCMs that allosterically potentiate NO have proven successful clinical trials peripheral indications, however, there are no reports directed at activity CNS. The aim this study develop CNS disorders, A library was synthesized, positive allosteric (PAMs) modulators, as assessed increasing pCREB SH-SY5Y human neuroblastoma cultures. Molecules were designed classical bioisosteric replacement, aiming desirable physiochemical properties diversity. GCM PAMs cGMP elevation reversal neurotoxicity induced 6-hydroxydopamine neuronal cells. One PAM, active culture, further tested memory deficits mice treated scopolamine, drug plasma measured. ligand site stimulators on remains definitively defined. Photoaffinity probes retained parent PAM order elucidate mode indicate other partners such compounds.