Preclinical Characterization of A-582941: A Novel α7 Neuronal Nicotinic Receptor Agonist with Broad Spectrum Cognition-Enhancing Properties
| Autor: | Kaitlin E. Browman, Arthur L. Nikkel, Richard Harris, Monika Håkerud, William H. Bunnelle, Paul J. Brackemeyer, David J. Anderson, Jennifer M. Frost, Sabine Halm, Jens Halvard Grønlien, Eva Spies, Liping Pan, Eric A.G. Blomme, Clark A. Briggs, Rosalind J. Helfrich, Ryan M. Fryer, Karla Drescher, Earl J. Gubbins, R. Scott Bitner, Ruth L. Martin, Kennan C. Marsh, Kirsten Thorin-Hagene, Stephani Otte, Peter Curzon, Murali Gopalakrishnan, John Malysz, Michael Meyer, Devalina Law, Gerard B. Fox, Hilde Ween, Dagmar Bury, Karin R. Tietje, Hongyu Xu, Pamela S. Puttfarcken, Angela L. Molesky, Kathy L. Kohlhaas, Holly M. Robb, Jeffrey F. Waring, Richard J. Radek |
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| Rok vydání: | 2008 |
| Předmět: |
Agonist
alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Hippocampus Review Receptors Nicotinic Cognition Physiology (medical) medicine Animals Humans Pyrroles Pharmacology (medical) Nicotinic Agonists Pharmacology Sensory gating Working memory medicine.disease Pyridazines Psychiatry and Mental health Neuropsychology and Physiological Psychology Nicotinic agonist medicine.anatomical_structure Memory consolidation Alzheimer's disease Psychology Neuroscience |
| Zdroj: | CNS Drug Reviews. 14:65-82 |
| ISSN: | 1527-3458 1080-563X |
| DOI: | 10.1111/j.1527-3458.2008.00037.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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