B-973, a novel piperazine positive allosteric modulator of the α7 nicotinic acetylcholine receptor

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The alpha7 (α7) nicotinic acetylcholine receptor is a therapeutic target for cognitive disorders. Here we describe 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide (B-973), a novel piperazine-containing molecule that acts as a positive allosteric modulator of the α7 receptor. We characterize the action of B-973 on the α7 receptor using electrophysiology and radioligand binding. At 0.1 mM acetylcholine, 1 μM B-973 potentiated peak acetylcholine-induced currents 6-fold relative to maximal acetylcholine (3 mM) and slowed channel desensitization, resulting in a 6900-fold increase in charge transfer. The EC50 of B-973 was approximately 0.3 μM at acetylcholine concentrations ranging from 0.03 to 3 mM. At a concentration of 1 μM, B-973 shifted the acetylcholine EC50 of peak currents from 0.30 mM in control to 0.007 mM. B-973 slowed channel deactivation upon acetylcholine removal (τ=50 s) and increased the affinity of the α7 agonist [3H]A-585539. In the absence of exogenously added acetylcholine, application of B-973 at concentrations >1 μM induced large methyllycaconitine-sensitive currents, suggesting B-973 can function as an Ago-PAM at high concentrations. B-973 will be a useful probe for investigating the biological consequences of increasing α7 receptor activity through allosteric modulation.

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