title: 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 EC50of 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 EC50of 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.
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Post-Munson
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Rick L
authors.initials: RL
authors.lastname: Pieschl
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Graef
authors.affiliation: Lead Discovery and Optimization, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Hendricson
authors.affiliation: Lead Discovery and Optimization, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knox
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Ivar M
authors.initials: IM
authors.lastname: McDonald
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Weed
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.affiliation: Lead Discovery and Optimization, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kiss
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ahlijanian
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA. Electronic address: herrjb42@gmail.com.
authors.forename: James
authors.initials: J
authors.lastname: Herrington
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D010666:Phenylpropionates / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C000617860:B-973 compound; D010666:Phenylpropionates; D010879:Piperazines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine
keywords: Allosteric modulation; Alzheimer's disease; Positive allosteric modulator; Schizophrenia; α7 Acetylcholine receptor