2. Academic Validation
  3. Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties

Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties

  • CNS Neurosci Ther. 2008 Spring;14(1):65-82. doi: 10.1111/j.1527-3458.2008.00037.x.
Karin R Tietje 1,  David J Anderson,  R Scott Bitner,  Eric A Blomme,  Paul J Brackemeyer,  Clark A Briggs,  Kaitlin E Browman,  Dagmar Bury,  Peter Curzon,  Karla U Drescher,  Jennifer M Frost,  Ryan M Fryer,  Gerard B Fox,  Jens Halvard Gronlien,  Monika Håkerud,  Earl J Gubbins,  Sabine Halm,  Richard Harris,  Rosalind J Helfrich,  Kathy L Kohlhaas,  Devalina Law,  John Malysz,  Kennan C Marsh,  Ruth L Martin,  Michael D Meyer,  Angela L Molesky,  Arthur L Nikkel,  Stephani Otte,  Liping Pan,  Pamela S Puttfarcken,  Richard J Radek,  Holly M Robb,  Eva Spies,  Kirsten Thorin-Hagene,  Jeffrey F Waring,  Hilde Ween,  Hongyu Xu,  Murali Gopalakrishnan,  William H Bunnelle
Affiliations

Affiliation

  • 1 Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
PMID: 18482100 DOI: 10.1111/j.1527-3458.2008.00037.x
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.

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