Development of an allosteric modulator functional assay and characterization of the nicotinic acetylcholine receptor alpha7 (nAChR α 7 ) positive modulator PNU‐120596

Clinical and pre‐clinical evidence suggests that stimulation of nAChR α 7 mediates improvements in cognitive function. A decline in cognitive function is associated with several neurodegenerative conditions including Alzheimer’s disease. In addition to the use of cholinomimetic drugs (subtype‐selective nicotinic and muscarinic agonists) and cholinesterase inhibitors (to increase cholinergic tone), positive allosteric modulation of nAChR α 7 is a strategy emerging in the literature. Benefits of allosteric modulation may include improved target selectivity, avoidance of receptor desensitization, and enhanced nicotinic receptor function when the cholinergic system is physiologically activated. Here we report on a functional assay amenable to high throughput screening that is capable of revealing positive allosteric modulators of the nAChR α 7 response to its physiological ligand, acetylcholine (ACh). We have characterized the effects of PNU‐120596 (a selective nAChR α 7 modulator) on responses to ACh, as well as nicotine and selective nAChR α 7 partial agonists GTS‐21 and 4OH‐GTS‐21. The activity of this modulator was examined in the parental cell line GH 4 C 1 , including its effect on the function of endogenous voltage‐gated calcium channels. Finally, we report on the ability of PNU‐120596 to influence striatal neurotransmitter release in synaptasomes.