2. Academic Validation
  3. Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

  • Eur J Med Chem. 2024 Dec 15:280:116981. doi: 10.1016/j.ejmech.2024.116981.
Jan Konecny 1,  Anna Misiachna 2,  Marketa Chvojkova 3,  Lenka Kleteckova 4,  Marharyta Kolcheva 2,  Martin Novak 5,  Lukas Prchal 5,  Marek Ladislav 2,  Katarina Hemelikova 2,  Jakub Netolicky 2,  Martina Hrabinova 1,  Tereza Kobrlova 5,  Jana Zdarova Karasova 1,  Jaroslav Pejchal 6,  Jakub Fibigar 6,  Zbynek Vecera 6,  Tomas Kucera 6,  Pavla Jendelova 2,  Petra Zahumenska 2,  Emily Langore 2,  Jovana Doderovic 2,  Yuan-Ping Pang 7,  Karel Vales 4,  Jan Korabecny 1,  Ondrej Soukup 8,  Martin Horak 9
Affiliations

Affiliations

  • 1 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 2 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 4, 14220, Prague, Czech Republic.
  • 3 National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
  • 4 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 4, 14220, Prague, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
  • 5 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 6 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 7 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, 55905, MN, USA.
  • 8 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
  • 9 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 4, 14220, Prague, Czech Republic. Electronic address: martin.horak@iem.cas.cz.
PMID: 39442339 DOI: 10.1016/j.ejmech.2024.116981
Abstract

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-d-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA Receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (∼90 % for GluN1/GluN2A), while 3l showed moderate inhibition (∼50 %). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [a,d][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

Keywords

Acetylcholinesterase; Alzheimer's disease; Electrophysiology; Ionotropic glutamate receptor; NMDA receptor; Neuroprotection.

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