Discovery of a highly potent, functionally-selective muscarinic M1 agonist, WAY-132983 using rational drug design and receptor modelling

Bioorg Med Chem Lett. 1999 Jul 19;9(14):1895-900. doi: 10.1016/s0960-894x(99)00313-3.

Abstract

Rational drug design utilizing a receptor homology model of the human muscarinic M1 receptor led to the discovery of the highly potent (Ki = 2 nM), efficacious, and in vivo functionally-selective M1 agonist, WAY-132983.

MeSH terms

  • Administration, Oral
  • Animals
  • Bridged-Ring Compounds / chemistry*
  • Bridged-Ring Compounds / pharmacology*
  • CHO Cells / metabolism
  • Carbachol / chemistry
  • Carbachol / metabolism
  • Carbachol / pharmacology
  • Cerebral Cortex / metabolism
  • Cognition Disorders / drug therapy
  • Computer Simulation
  • Cricetinae
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Macaca mulatta
  • Maze Learning / drug effects
  • Models, Molecular
  • Muscarinic Agonists / chemistry*
  • Muscarinic Agonists / pharmacology*
  • Phosphatidylinositols / metabolism
  • Protein Conformation
  • Pyrazines / chemistry*
  • Pyrazines / pharmacology*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rats
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / chemistry
  • Receptors, Muscarinic / metabolism*
  • Salivation / drug effects
  • Structure-Activity Relationship
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology

Substances

  • Bridged-Ring Compounds
  • Muscarinic Agonists
  • Phosphatidylinositols
  • Pyrazines
  • Pyridines
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • Thiadiazoles
  • WAY 132983
  • Carbachol
  • xanomeline