Assays and screens

A synaptosome-based assay of long-term synaptic potentiation could be used to screen therapies to treat AD. The assay involved isolating synaptosomes from frozen, postmortem parietal cortex samples from AD patients and unaffected organ donors; treating the synaptosomes with glycine and potassium chloride to stimulate long-term potentiation (LTP); and quantifying levels of the surface levels of AMPA 1 glutamate receptor (GRIA1; GLUR1) and the β-isoform of neurexin 1 (NRXN1) with flow cytometry to measure LTP levels. In postmortem parietal cortex samples, the method detected lower levels of LTP in samples from AD patients than in samples from unaffected organ donors. In the assay based on patient-derived synaptosomes, screening of 18 compounds and compound combinations identified two combinations -- the soluble guanylate cyclase (sGC) activator cinaciguat plus the phosphodiesterase-5 (PDE-5) inhibitor Levitra vardenafil, or cinaciguat plus a PDE-9 inhibitor tool compound -- that increased LTP compared with vehicle. Next steps include using the assay to measure EC₅₀ values and other pharmacodynamic parameters of compounds that increase long-term potentiation.

Bayer AG has cinaciguat (BAY 58-2667) in Phase II testing for acute heart failure. ...