Abstract
We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats.
Keywords:
8-Azatetrahydroquinolone; Antipsychotic agents; M(1) muscarinic acetylcholine receptor; M(4) muscarinic acetylcholine receptor; Schizophrenia; Selective agonist.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Antipsychotic Agents / chemical synthesis
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / pharmacology*
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Behavior, Animal / drug effects
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Hydroquinones / chemical synthesis*
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Hydroquinones / chemistry
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Hydroquinones / pharmacology*
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Molecular Structure
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Rats
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Receptor, Muscarinic M1 / agonists*
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Receptor, Muscarinic M4 / agonists*
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Structure-Activity Relationship
Substances
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Antipsychotic Agents
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Aza Compounds
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Hydroquinones
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Receptor, Muscarinic M1
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Receptor, Muscarinic M4
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hydroquinone