title: Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains.
abstract: Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Weed
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bookbinder
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Polino
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Keavy
authors.affiliation: Behavioral and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge, UK.|Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
authors.forename: Rudolf N
authors.identifier: http://orcid.org/0000-0002-8751-5167
authors.initials: RN
authors.lastname: Cardinal
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Simmermacher-Mayer
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Fu-ni L
authors.initials: FN
authors.lastname: Cometa
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Dalton
authors.initials: D
authors.lastname: King
authors.affiliation: Discovery Chemistry, Biocon Bristol-Myers Squibb Research & Development Center, Bangalore, India.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Thangathirupathy
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001966:Bromine / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism; D015331:Cohort Studies; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008251:Macaca; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: C585977:AZD6765; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; C121001:NR2B NMDA receptor; D010627:Phenethylamines; D010880:Piperidines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C009106:Psychoverlan; D007649:Ketamine; C095106:traxoprodil mesylate; D008274:Magnesium; D001966:Bromine