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.

journal_name

CNS Neurosci Ther

authors

Tietje KR,Anderson DJ,Bitner RS,Blomme EA,Brackemeyer PJ,Briggs CA,Browman KE,Bury D,Curzon P,Drescher KU,Frost JM,Fryer RM,Fox GB,Gronlien JH,Håkerud M,Gubbins EJ,Halm S,Harris R,Helfrich RJ,Kohlhaas KL,Law D,M

doi

10.1111/j.1527-3458.2008.00037.x

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

65-82

issue

1

eissn

1755-5930

issn

1755-5949

pii

CNS037

journal_volume

14

pub_type

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