Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects
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.
Authors
- Petra Zahumenská (ORCID: https://orcid.org/0009-0002-1869-3864)
- Ondřej Soukup (ORCID: https://orcid.org/0000-0001-6376-8701)
- Lenka Kletečková (ORCID: https://orcid.org/0000-0002-7499-2757)
- Katarína Hemelíková
- Karel Valeš (ORCID: https://orcid.org/0000-0001-7892-4535)
- Markéta Chvojková (ORCID: https://orcid.org/0000-0002-7630-7362)
- Martin Hořák (ORCID: https://orcid.org/0000-0002-4359-051X)
- Emily Langore
- Jaroslav Pejchal (ORCID: https://orcid.org/0000-0003-2228-7922)
- Marek Ladislav (ORCID: https://orcid.org/0000-0002-5396-9005)
- Jakub Netolický (ORCID: https://orcid.org/0000-0001-7650-7172)
- Martin Novák (ORCID: https://orcid.org/0000-0002-3450-1220)
- Lukáš Prchal (ORCID: https://orcid.org/0000-0001-9698-4478)
- Tereza Kobrlová (ORCID: https://orcid.org/0000-0002-4445-0287)
- Jan Konečný (ORCID: https://orcid.org/0000-0003-4155-8791)
- Jana Žďárová Karasová (ORCID: https://orcid.org/0000-0003-0891-9591)
- Yuan‐Ping Pang (ORCID: https://orcid.org/0000-0003-0838-2560)
- Martina Hrabinová (ORCID: https://orcid.org/0000-0002-9428-4109)
- Tomáš Kučera (ORCID: https://orcid.org/0000-0001-6650-1738)
- Pavla Jendelová (ORCID: https://orcid.org/0000-0002-4644-9212)
- Marharyta Kolcheva (ORCID: https://orcid.org/0000-0002-1722-169X)
- Jan Korábečný (ORCID: https://orcid.org/0000-0001-6977-7596)
- Jakub Fibigar (ORCID: https://orcid.org/0000-0002-5170-3668)
- Zbyněk Večeřa (ORCID: https://orcid.org/0000-0003-3137-9597)
- Anna Misiachna
- Jovana Doderovic
Institutions
- Mayo Clinic (US)
- Czech Academy of Sciences (CZ)
- Institute of Microbiology (BY)
- Czech Academy of Sciences, Institute of Experimental Medicine (CZ)
- University Hospital Hradec Králové (CZ)
- National Institute of Mental Health (CZ)
- University of Defence (CZ)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1016/j.ejmech.2024.116981
- Citations
- 1
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.27
Funders
- Univerzita Hradec Králové
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Akademie Věd České Republiky