Inhibition of in vivo [(3)H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice

European Journal of Pharmacology
Alda FernandesYu-Wen Li

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [(3)H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [(3)H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [(3)H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [(3)H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with...Continue Reading

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Citations

Feb 26, 2019·Frontiers in Neuroscience·Jinping LiuYan Wu
Mar 10, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Ting LeiHua Zhao
Feb 12, 2021·Biochemical Pharmacology·Martina KaniakovaOndrej Soukup
Dec 12, 2020·The International Journal of Neuropsychopharmacology·Lili Veronika NagyIstván Hernádi
May 28, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Xiaofei SheZhewen Dong

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