title: The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction.
abstract: Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.
authors.affiliation: Medicines Discovery and Development, GlaxoSmithKline Clinical Unit, Cambridge, UK. pradeep.j.nathan@gsk.com
authors.forename: Pradeep J
authors.initials: PJ
authors.lastname: Nathan
authors.forename: Jeannette
authors.initials: J
authors.lastname: Watson
authors.forename: Jesper
authors.initials: J
authors.lastname: Lund
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
authors.forename: Gary
authors.initials: G
authors.lastname: Peters
authors.forename: Chris M
authors.initials: CM
authors.lastname: Dodds
authors.forename: Bridget
authors.initials: B
authors.lastname: Swirski
authors.forename: Philip
authors.initials: P
authors.lastname: Lawrence
authors.forename: Graham D
authors.initials: GD
authors.lastname: Bentley
authors.forename: Barry V
authors.initials: BV
authors.lastname: O'Neill
authors.forename: Jon
authors.initials: J
authors.lastname: Robertson
authors.forename: Stephen
authors.initials: S
authors.lastname: Watson
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Jones
authors.forename: Paul
authors.initials: P
authors.lastname: Maruff
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Croft
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000328:Adult; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D016739:Behavior, Addictive / Q000188:drug therapy / Q000523:psychology*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy / Q000523:psychology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D008875:Middle Aged; D009538:Nicotine; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000502:physiology; D012907:Smoking / Q000523:psychology; D016540:Smoking Cessation / Q000523:psychology*; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; C568644:GSK 1034702; D043643:Receptor, Muscarinic M1; D009538:Nicotine