Open AccessPreclinical Characterization of A‐582941: A Novel α7 Neuronal Nicotinic Receptor Agonist with Broad Spectrum Cognition‐Enhancing Properties
Author(s) -
Tietje Karin R.,
Anderson David J.,
Bitner R. Scott,
Blomme Eric A.,
Brackemeyer Paul J.,
Briggs Clark A.,
Browman Kaitlin E.,
Bury Dagmar,
Curzon Peter,
Drescher Karla U.,
Frost Jennifer M.,
Fryer Ryan M.,
Fox Gerard B.,
Gronlien Jens Halvard,
Håkerud Monika,
Gubbins Earl J.,
Halm Sabine,
Harris Richard,
Helfrich Rosalind J.,
Kohlhaas Kathy L.,
Law Devalina,
Malysz John,
Marsh Kennan C.,
Martin Ruth L.,
Meyer Michael D.,
Molesky Angela L.,
Nikkel Arthur L.,
Otte Stephani,
Pan Liping,
Puttfarcken Pamela S.,
Radek Richard J.,
Robb Holly M.,
Spies Eva,
ThorinHagene Kirsten,
Waring Jeffrey F.,
Ween Hilde,
Xu Hongyu,
Gopalakrishnan Murali,
Bunnelle William H.
Publication year - 2008
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/j.1527-3458.2008.00037.x
Subject(s) - neuroscience , nicotinic agonist , partial agonist , prefrontal cortex , memory consolidation , agonist , cognition , psychology , hippocampus , pharmacology , medicine , receptor
Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the α7 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 α7 nAChR agonist, A‐582941. A‐582941 was found to exhibit high‐affinity binding and partial agonism at α7 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 α7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.