Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties.
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.
Tietje
Karin R
KR
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Anderson
David J
DJ
Bitner
R Scott
RS
Blomme
Eric A
EA
Brackemeyer
Paul J
PJ
Briggs
Clark A
CA
Browman
Kaitlin E
KE
Bury
Dagmar
D
Curzon
Peter
P
Drescher
Karla U
KU
Frost
Jennifer M
JM
Fryer
Ryan M
RM
Fox
Gerard B
GB
Gronlien
Jens Halvard
JH
Håkerud
Monika
M
Gubbins
Earl J
EJ
Halm
Sabine
S
Harris
Richard
R
Helfrich
Rosalind J
RJ
Kohlhaas
Kathy L
KL
Law
Devalina
D
Malysz
John
J
Marsh
Kennan C
KC
Martin
Ruth L
RL
Meyer
Michael D
MD
Molesky
Angela L
AL
Nikkel
Arthur L
AL
Otte
Stephani
S
Pan
Liping
L
Puttfarcken
Pamela S
PS
Radek
Richard J
RJ
Robb
Holly M
HM
Spies
Eva
E
Thorin-Hagene
Kirsten
K
Waring
Jeffrey F
JF
Ween
Hilde
H
Xu
Hongyu
H
Gopalakrishnan
Murali
M
Bunnelle
William H
WH
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
C524029:A-582941; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011724:Pyridazines; D011758:Pyrroles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor