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

• Published in: European journal of pharmacology 2017-03, Vol.799, p.16-25
• Main Authors: Post-Munson, Debra J., Pieschl, Rick L., Molski, Thaddeus F., Graef, John D., Hendricson, Adam W., Knox, Ronald J., McDonald, Ivar M., Olson, Richard E., Macor, John E., Weed, Michael R., Bristow, Linda J., Kiss, Laszlo, Ahlijanian, Michael K., Herrington, James
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Allosteric modulation; Allosteric Regulation - drug effects; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Alzheimer's disease; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Kinetics; Phenylpropionates - pharmacology; Piperazines - pharmacology; Positive allosteric modulator; Schizophrenia; α7 Acetylcholine receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.01.037

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 0.1mM acetylcholine, 1μM B-973 potentiated peak acetylcholine-induced currents 6-fold relative to maximal acetylcholine (3mM) and slowed channel desensitization, resulting in a 6900-fold increase in charge transfer. The EC50 of B-973 was approximately 0.3μM at acetylcholine concentrations ranging from 0.03 to 3mM. At a concentration of 1μM, B-973 shifted the acetylcholine EC50 of peak currents from 0.30mM in control to 0.007mM. B-973 slowed channel deactivation upon acetylcholine removal (τ=50s) and increased the affinity of the α7 agonist [3H]A-585539. In the absence of exogenously added acetylcholine, application of B-973 at concentrations >1μM 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. [Display omitted]