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

CNS Neurosci Ther. Spring 2008;14(1):65-82. 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.

Publication types

  • Review

MeSH terms

  • Animals
  • Cognition / drug effects*
  • Humans
  • Nicotinic Agonists / pharmacology*
  • Pyridazines / pharmacology*
  • Pyrroles / pharmacology*
  • Receptors, Nicotinic / physiology*
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • A-582941
  • Chrna7 protein, human
  • Nicotinic Agonists
  • Pyridazines
  • Pyrroles
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor