PT - JOURNAL ARTICLE AU - Elena Popugaeva AU - Daria Cherniuk AU - Hua Zhang AU - Tatiana Postnikova AU - Karina Pac AU - Elena Fedorova AU - Vladimir Poroikov AU - Alexey Zaitsev AU - Ilya Bezprozvanny TI - Derivatives of Piperazines as Potential Therapeutic Agents for Alzheimer's Disease AID - 10.1124/mol.118.114348 DP - 2019 Jan 01 TA - Molecular Pharmacology PG - mol.118.114348 4099 - http://molpharm.aspetjournals.org/content/early/2019/01/28/mol.118.114348.short 4100 - http://molpharm.aspetjournals.org/content/early/2019/01/28/mol.118.114348.full AB - Alzheimer's disease is the neurodegenerative disorder that is a major cause of dementia in the elderly. There is no cure against AD. We have recently discovered novel TRPC6-mediated intracellular signaling pathway that regulates stability of dendritic spines and plays a role in memory formation. We have previously shown that TRPC6 agonists exert beneficial effects in models of AD and may serve as lead compounds for development of AD therapeutic agents. In the current study, we used Integrity database to search for additional TRPC6 agonists. We have selected four compounds to study them as potential neuroprotective agents. We applied bioinformatical analyses to test basic pharmacological properties of selected compounds. We performed in vitro screening of these compounds to validate their ability to protect mushroom spines from amyloid toxicity and determined that two of these compounds exert neuroprotective effects in the nanomolar concentration range. We have chosen one of these compounds (piperazine, PPZ) for further testing. In agreement with previously published data, we have shown that PPZ activates TRPC6 channels. We demonstrated that neuroprotective mechanism of investigated PPZ is based on activation of neuronal store-operated calcium entry (nSOCE) in spines. We have shown that PPZ restores long-term potentiation (LTP) induction in 6 months old 5xFAD mouse hippocampal slices. Obtained results suggest that PPZ and its derivatives are potential lead molecules for development of AD therapeutic agents.