Inhibition of in vivo [(3)H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice.
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 ketamine (10mg/kg, i.p.) and Ro 25-6981(10mg/kg, i.p.) produced a level of inhibition of in vivo [(3)H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [(3)H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit.
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Alda
A
Fernandes
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Trevor
T
Wojcik
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Praveena
P
Baireddy
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Rick
R
Pieschl
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Amy
A
Newton
Radiosynthesis, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Yuan
Y
Tian
Radiosynthesis, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Yang
Y
Hong
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Linda
L
Bristow
Genetically-Defined Diseases, 5 Research Parkway, Wallingford, CT 06492-7660, USA. Electronic address: yu-wen.li@bms.com.
Yu-Wen
YW
Li
D000818:Animals; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics*; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate
Antagonist; Channel blocker; GluN2B; NMDA; Occupancy; Radioligand binding