Development of a more highly selective M(1) antagonist from the continued optimization of the MLPCN Probe ML012

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1044-8. doi: 10.1016/j.bmcl.2011.11.110. Epub 2011 Dec 6.

Abstract

This Letter describes the continued optimization of an MLPCN probe molecule (ML012) through an iterative parallel synthesis approach. After exploring extensive modifications throughout the parent structure, we arrived at a more highly M(1)-selective antagonist, compound 13l (VU0415248). Muscarinic subtype selectivity across all five human and rat receptors for 13l, along with rat selectivity for the lead compound (ML012), is presented.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Probes / chemical synthesis
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Molecular Structure
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Rats
  • Receptor, Muscarinic M1 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Molecular Probes
  • Quinolines
  • Receptor, Muscarinic M1
  • Sulfonamides
  • VU0415248