title: MK-7128, a novel CB1 receptor inverse agonist, improves scopolamine-induced learning and memory deficits in mice.
abstract: Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.
authors.affiliation: Neuroscience Drug Discovery, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dillon
authors.forename: Laura S
authors.initials: LS
authors.lastname: Lubbers
authors.forename: Mitchell T
authors.initials: MT
authors.lastname: Ferguson
authors.forename: Julie Z
authors.initials: JZ
authors.lastname: Lao
authors.forename: Ruey-Ruey C
authors.initials: RR
authors.lastname: Huang
authors.forename: Jing C
authors.initials: JC
authors.lastname: Xiao
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Kathleen
authors.initials: K
authors.lastname: Rupprecht
authors.forename: Shouwu
authors.initials: S
authors.lastname: Miao
authors.forename: Blake A
authors.initials: BA
authors.lastname: Rowe
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kornecook
authors.forename: Jean-Cosme
authors.initials: JC
authors.lastname: Dodart
mesh_terms: D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D012601:Scopolamine
chemical_list: C558877:3-(1-(1-((4-chlorophenyl)(3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)methyl)azetidin-3-yl)-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile; D001384:Azetidines; D010069:Oxadiazoles; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D012601:Scopolamine