Structure-Based Design and Discovery of New M 2 Receptor Agonists

J Med Chem. 2017 Nov 22;60(22):9239-9250. doi: 10.1021/acs.jmedchem.7b01113. Epub 2017 Nov 13.

Abstract

Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.

Publication types

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

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Arrestin / metabolism
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • CHO Cells
  • Carbachol / pharmacology
  • Cricetulus
  • Drug Design
  • HEK293 Cells
  • Humans
  • Isoxazoles / pharmacology
  • Ligands
  • Molecular Docking Simulation
  • Muscarinic Agonists / chemical synthesis
  • Muscarinic Agonists / chemistry
  • Muscarinic Agonists / pharmacology*
  • N-Methylscopolamine / chemistry
  • Quaternary Ammonium Compounds / chemical synthesis
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology
  • Receptor, Muscarinic M1 / agonists
  • Receptor, Muscarinic M1 / chemistry
  • Receptor, Muscarinic M1 / metabolism
  • Receptor, Muscarinic M2 / agonists*
  • Receptor, Muscarinic M2 / chemistry
  • Receptor, Muscarinic M2 / metabolism
  • Receptor, Muscarinic M3 / agonists
  • Receptor, Muscarinic M3 / chemistry
  • Receptor, Muscarinic M3 / metabolism
  • Receptors, Nicotinic / chemistry
  • Tritium

Substances

  • 2-(2,3-dihydrobenzofuran-6-yl)-N,N,N-trimethylethan-1-aminium
  • Arrestin
  • Benzofurans
  • Isoxazoles
  • Ligands
  • Muscarinic Agonists
  • Quaternary Ammonium Compounds
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Nicotinic
  • iperoxo
  • nicotinic receptor alpha4beta2
  • Tritium
  • Carbachol
  • Acetylcholine
  • N-Methylscopolamine