Synthesis and pharmacological evaluation of analogues of benzyl quinolone carboxylic acid (BQCA) designed to bind irreversibly to an allosteric site of the M ₁ muscarinic acetylcholine receptor

J Med Chem. 2014 Jun 26;57(12):5405-18. doi: 10.1021/jm500556a. Epub 2014 Jun 5.


Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Animals
  • CHO Cells
  • Cricetulus
  • Crystallography, X-Ray
  • Humans
  • Isothiocyanates / chemical synthesis
  • Isothiocyanates / chemistry*
  • Isothiocyanates / pharmacology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Quinolones / chemical synthesis
  • Quinolones / chemistry*
  • Quinolones / pharmacology
  • Radioligand Assay
  • Receptor, Muscarinic M1 / metabolism*
  • Structure-Activity Relationship


  • 1-(4-isothiocyanatobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  • Isothiocyanates
  • Quinolones
  • Receptor, Muscarinic M1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3