@article{92640d84f6c34f33ba5b1763357f0f11,
title = "Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease",
abstract = "Currently, of the few accessible symptomatic therapies for Alzheimer's disease (AD), memantine is the only N-methyl-d-aspartate receptor (NMDAR) blocker approved by the FDA. This work further explores a series of memantine analogs featuring a benzohomoadamantane scaffold. Most of the newly synthesized compounds block NMDARs in the micromolar range, but with lower potency than previously reported hit IIc, results that were supported by molecular dynamics simulations. Subsequently, electrophysiological studies with the more potent compounds allowed classification of IIc, a low micromolar, uncompetitive, voltage-dependent, NMDAR blocker, as a memantine-like compound. The excellent in vitro DMPK properties of IIc made it a promising candidate for in vivo studies in Caenorhabditis elegans (C. elegans) and in the 5XFAD mouse model of AD. Administration of IIc or memantine improved locomotion and rescues chemotaxis behavior in C. elegans. Furthermore, both compounds enhanced working memory in 5XFAD mice and modified NMDAR and CREB signaling, which may prevent synaptic dysfunction and modulate neurodegenerative progression.",
keywords = "Alzheimer's disease, Benzohomoadamantane, Caenorhabditis elegans, Electrophysiology, 5XFAD, Memantine analogs, Alzheimer's disease, Benzohomoadamantane, Caenorhabditis elegans, Electrophysiology, 5XFAD, Memantine analogs, Alzheimer's disease, Benzohomoadamantane, Caenorhabditis elegans, Electrophysiology, 5XFAD, Memantine analogs",
author = "Turcu, \{Andreea L.\} and J{\'u}lia Companys-Alemany and Phillips, \{Matthew B.\} and Patel, \{Dhilon S.\} and Christian Gri{\~n}{\'a}n-Ferr{\'e} and Loza, \{M. Isabel\} and Brea, \{Jos{\'e} M.\} and Bel{\'e}n P{\'e}rez and David Soto and Sureda, \{Francesc X.\} and Kurnikova, \{Maria G.\} and Johnson, \{Jon W.\} and Merc{\`e} Pall{\`a}s and Santiago V{\'a}zquez",
note = "Funding Information: This research was funded by the Spanish Ministerio de Econom{\'i}a, Industria y Competitividad (Grant SAF2017-82771-R to S.V. and PID2019-106285RB-I00 to M.P.), the Mar{\'i}a de Maeztu Unit of Excellence (Institute of Neurosciences, Universitat de Barcelona , MDM-2017-0729 , to M.P. and D.S.), and 2017SGR106 ( AGAUR , Catalonia to S.V. and M.P.), the Spanish Ministerio de Ciencia e Innovaci{\'o}n (Grant PID2020-119932 GB-I00/AEI /10.13039/5011000011033 to D. S.), the European Regional Development Fund ( ERDF ), the Xunta de Galicia ( ED431G 2019/02 and ED431C 2018/21 ), and the United States National Institutes of Health (Grant R01AG065594 to J.W.J., M.G.K., and S.V; Grant F31NS113477 to M.B.P). J.C.-A acknowledges the Spanish Ministerio de Ciencia e Innovaci{\'o}n for a FPI fellowship ( MDM-2017-0729-19-2 ). A.L.T. acknowledges a PhD fellowship (FPU grant) from the Spanish Ministerio de Educaci{\'o}n, Cultura y Deporte and the Spanish Society of Medicinal Chemistry (SEQT) and Enantia S. L. for an “Award for Novel Researchers in the Discovery and Development of New Drugs”. Computational work used the Extreme Science and Engineering Discovery Environment (XSEDE) Bridges 2 at Pittsburgh Supercomputing Center, allocation to M.G.K. TG-MCB180173, which is supported by the United States National Science Foundation grant number ACI-1548562 . Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jun,
day = "5",
doi = "10.1016/j.ejmech.2022.114354",
language = "English",
volume = "236",
}