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Br J Pharmacol. 2012 Sep;167(1):164-82. doi: 10.1111/j.1476-5381.2012.01989.x.

Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.

Author information

1
NeuroSearch A/S, Drug Discovery, Ballerup, Denmark.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

PMID:
22506660
PMCID:
PMC3448921
DOI:
10.1111/j.1476-5381.2012.01989.x
[Indexed for MEDLINE]
Free PMC Article

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