RT Journal Article SR Electronic T1 Derivatives of Piperazines as Potential Therapeutic Agents for Alzheimer’s Disease JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 337 OP 348 DO 10.1124/mol.118.114348 VO 95 IS 4 A1 Elena Popugaeva A1 Daria Chernyuk A1 Hua Zhang A1 Tatyana Y. Postnikova A1 Karina Pats A1 Elena Fedorova A1 Vladimir Poroikov A1 Aleksey V. Zaitsev A1 Ilya Bezprozvanny YR 2019 UL http://molpharm.aspetjournals.org/content/95/4/337.abstract AB Alzheimer’s disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the elderly. There is no cure against AD. We have recently discovered a novel transient receptor potential canonical 6 (TRPC6)–mediated intracellular signaling pathway that regulates the 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 the Clarivate Analytics Integrity database to search for additional TRPC6 agonists. We selected four compounds to study as potential neuroprotective agents. We applied bioinformatics analyses to test the basic pharmacological properties of the 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 potentiates TRPC6 channels. We demonstrated that the neuroprotective mechanism of the investigated PPZ is based on activation of neuronal store-operated calcium entry in spines. We have shown that PPZ restores long-term potentiation induction in 6-month-old 5xFAD mouse hippocampal slices. The obtained results suggest that PPZ and its derivatives are potential lead molecules for development of AD therapeutic agents.