Abstract
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
MeSH terms
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Administration, Oral
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Animals
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Humans
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Inhibitory Concentration 50
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Male
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Models, Molecular
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Nicotinic Agonists / administration & dosage
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Nicotinic Agonists / chemical synthesis*
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Nicotinic Agonists / pharmacokinetics
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Nicotinic Agonists / pharmacology*
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Protein Conformation
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Pyridines / administration & dosage
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Rats
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Receptors, Nicotinic / chemistry
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Receptors, Nicotinic / metabolism*
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Structure-Activity Relationship
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Substrate Specificity
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Urea / administration & dosage
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacokinetics
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Urea / pharmacology*
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alpha7 Nicotinic Acetylcholine Receptor
Substances
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1-(6-(4-fluorophenyl)pyridin-3-yl)-3-(4-piperidin-1-ylbutyl)urea
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Chrna7 protein, human
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Chrna7 protein, rat
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Nicotinic Agonists
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Pyridines
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Receptors, Nicotinic
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alpha7 Nicotinic Acetylcholine Receptor
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Urea