Identification of N-substituted 8-azatetrahydroquinolone derivatives as selective and orally active M(1) and M(4) muscarinic acetylcholine receptors agonists

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4644-7. doi: 10.1016/j.bmcl.2013.06.013. Epub 2013 Jun 13.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Behavior, Animal / drug effects
  • Hydroquinones / chemical synthesis*
  • Hydroquinones / chemistry
  • Hydroquinones / pharmacology*
  • Molecular Structure
  • Rats
  • Receptor, Muscarinic M1 / agonists*
  • Receptor, Muscarinic M4 / agonists*
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Aza Compounds
  • Hydroquinones
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M4
  • hydroquinone