Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

• Published in: European journal of medicinal chemistry 2024-12, Vol.280, p.116981, Article 116981
• Main Authors: Konecny, Jan, Misiachna, Anna, Chvojkova, Marketa, Kleteckova, Lenka, Kolcheva, Marharyta, Novak, Martin, Prchal, Lukas, Ladislav, Marek, Hemelikova, Katarina, Netolicky, Jakub, Hrabinova, Martina, Kobrlova, Tereza, Karasova, Jana Zdarova, Pejchal, Jaroslav, Fibigar, Jakub, Vecera, Zbynek, Kucera, Tomas, Jendelova, Pavla, Zahumenska, Petra, Langore, Emily, Doderovic, Jovana, Pang, Yuan-Ping, Vales, Karel, Korabecny, Jan, Soukup, Ondrej, Horak, Martin
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alzheimer's disease; Animals; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Electrophysiology; Humans; Ionotropic glutamate receptor; Male; Molecular Structure; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; NMDA receptor; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116981

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. [Display omitted] •Dizocilpine derivatives inhibit NMDA receptors in a voltage-dependent manner.•New compounds lack the psychomimetic effects associated with the parent dizocilpine.•Compounds 3l and 6f effectively penetrate the blood-brain barrier.•Compound 3l reduces hippocampal damage in an NMDA-induced neurodegeneration model.