7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
30099049
DOI
10.1016/j.neuropharm.2018.08.010
PII: S0028-3908(18)30487-8
Knihovny.cz E-zdroje
- Klíčová slova
- Behavioural experiment, Electrophysiology, Glutamate receptor, Human pathogenic mutation, Ion channel, Pharmacology,
- MeSH
- dizocilpinmaleát antagonisté a inhibitory farmakologie MeSH
- hipokampus účinky léků MeSH
- krysa rodu Rattus MeSH
- kultivované buňky MeSH
- lidé MeSH
- lokomoce účinky léků MeSH
- memantin farmakologie MeSH
- mutace MeSH
- neurony účinky léků fyziologie MeSH
- neuroprotektivní látky farmakologie MeSH
- prepulsní inhibice účinky léků MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory genetika MeSH
- takrin analogy a deriváty farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 7-methoxytacrine MeSH Prohlížeč
- dizocilpinmaleát MeSH
- memantin MeSH
- neuroprotektivní látky MeSH
- receptory N-methyl-D-aspartátu MeSH
- takrin MeSH
N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS), and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials (including memantine) and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine (tacrine; THA) was the first approved drug for Alzheimer's disease (AD) treatment. 7-methoxyderivative of THA (7-MEOTA) is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293 cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are "foot-in-the-door" open-channel blockers of GluN1/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC50 values for THA and 7-MEOTA exhibited the GluN1/GluN2A < GluN1/GluN2B < GluN1/GluN2C = GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluN1/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a "foot-in-the-door" open-channel blocker of GluN1/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDARs was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs.
Institute of Physiology of the Czech Academy of Sciences Videnska 1083 14220 Prague 4 Czech Republic
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