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

Abstract：

: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.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Post-Munson DJ,Pieschl RL,Molski TF,Graef JD,Hendricson AW,Knox RJ,McDonald IM,Olson RE,Macor JE,Weed MR,Bristow LJ,Kiss L,Ahlijanian MK,Herrington J

doi

10.1016/j.ejphar.2017.01.037

subject

Has Abstract

pub_date

2017-03-15 00:00:00

pages

16-25

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(17)30046-8

journal_volume

799

pub_type

杂志文章

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