title: Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.
abstract: OBJECTIVE
  Positive allosteric modulation of α4β2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively.
  
  
  METHODS
  Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+)  imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats.
  
  
  RESULTS
  NS9283 was shown to increase agonist-evoked response amplitude of (α4)(3) (β2)(2)  nACh receptors in electrophysiology paradigms. (α2)(3) (β2)(2) , (α2)(3) (β4)(2)  and (α4)(3) (β4)(2)  were modulated to comparable extents, but no effects were detected at α3-containing or any 2α : 3β stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHβE-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors.
  
  
  CONCLUSIONS
  These results provide compelling evidence that positive allosteric modulators acting at the (α4)(3) (β2)(2)  nACh receptors can augment activity across a broad range of cognitive domains, and that α4β2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.
authors.affiliation: NeuroSearch A/S, Drug Discovery, Ballerup, Denmark.
authors.forename: D B
authors.initials: DB
authors.lastname: Timmermann
authors.forename: K
authors.initials: K
authors.lastname: Sandager-Nielsen
authors.forename: T
authors.initials: T
authors.lastname: Dyhring
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: A-M
authors.initials: AM
authors.lastname: Jacobsen
authors.forename: E Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: M
authors.initials: M
authors.lastname: Grunnet
authors.forename: J K
authors.initials: JK
authors.lastname: Christensen
authors.forename: D
authors.initials: D
authors.lastname: Peters
authors.forename: K
authors.initials: K
authors.lastname: Kohlhaas
authors.forename: G M
authors.initials: GM
authors.lastname: Olsen
authors.forename: P K
authors.initials: PK
authors.lastname: Ahring
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010069:Oxadiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D021122:Protein Subunits / Q000502:physiology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology*; D021641:Recognition, Psychology / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: C561896:3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D021122:Protein Subunits; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine