title: Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties.
abstract: Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Karin R
authors.initials: KR
authors.lastname: Tietje
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: R Scott
authors.initials: RS
authors.lastname: Bitner
authors.forename: Eric A
authors.initials: EA
authors.lastname: Blomme
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brackemeyer
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Browman
authors.forename: Dagmar
authors.initials: D
authors.lastname: Bury
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authors.lastname: Curzon
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authors.initials: KU
authors.lastname: Drescher
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authors.initials: JM
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authors.initials: RM
authors.lastname: Fryer
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Jens Halvard
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authors.lastname: Gronlien
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authors.lastname: Håkerud
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Gubbins
authors.forename: Sabine
authors.initials: S
authors.lastname: Halm
authors.forename: Richard
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authors.lastname: Harris
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Helfrich
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: Devalina
authors.initials: D
authors.lastname: Law
authors.forename: John
authors.initials: J
authors.lastname: Malysz
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
authors.forename: Angela L
authors.initials: AL
authors.lastname: Molesky
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Nikkel
authors.forename: Stephani
authors.initials: S
authors.lastname: Otte
authors.forename: Liping
authors.initials: L
authors.lastname: Pan
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Puttfarcken
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Radek
authors.forename: Holly M
authors.initials: HM
authors.lastname: Robb
authors.forename: Eva
authors.initials: E
authors.lastname: Spies
authors.forename: Kirsten
authors.initials: K
authors.lastname: Thorin-Hagene
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.forename: Hilde
authors.initials: H
authors.lastname: Ween
authors.forename: Hongyu
authors.initials: H
authors.lastname: Xu
authors.forename: Murali
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authors.lastname: Gopalakrishnan
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D006801:Humans; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C524029:A-582941; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011724:Pyridazines; D011758:Pyrroles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor