Preclinical Characterization of A-582941: A Novel alpha 7 Neuronal Nicotinic Receptor Agonist with Broad Spectrum Cognition-Enhancing Properties

• Published in: CNS neuroscience & therapeutics Vol. 14; no. 1; pp. 65 - 82
• Main Authors: Tietje, Karin R, Anderson, David J, Bitner, RScott, 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, Haakerud, 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, Thorin-Hagene, Kirsten, Waring, Jeffrey F, Ween, Hilde, Xu, Hongyu, Gopalakrishnan, Murali, Bunnelle, William H
• Format: Journal Article
• Language: English
• Published: 01.03.2008
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/j.1755-5949.2008.00037.x

Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha 7 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 alpha 7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha 7 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 alpha 7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.