Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists

Bioorg Med Chem Lett. 2008 Feb 1;18(3):885-90. doi: 10.1016/j.bmcl.2007.12.051. Epub 2008 Jan 4.

Abstract

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Combinatorial Chemistry Techniques
  • Dose-Response Relationship, Drug
  • Dystonia / drug therapy
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Molecular Structure
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / pharmacokinetics
  • Muscarinic Antagonists / pharmacology*
  • Parkinson Disease / drug therapy
  • Receptor, Muscarinic M1 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Muscarinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Heterocyclic Compounds
  • Muscarinic Antagonists
  • Receptor, Muscarinic M1
  • Receptors, G-Protein-Coupled
  • Receptors, Muscarinic