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

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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 Ca2+ 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.

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