Design and synthesis of a novel series of 1,2-disubstituted cyclopentanes as small, potent potentiators of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors

J Med Chem. 2002 May 9;45(10):2101-11. doi: 10.1021/jm0105474.

Abstract

2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).

MeSH terms

  • Cell Line
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology
  • Excitatory Amino Acid Agents / chemical synthesis*
  • Excitatory Amino Acid Agents / chemistry
  • Excitatory Amino Acid Agents / pharmacology
  • Glutamic Acid / pharmacology
  • Humans
  • Receptors, AMPA / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Cyclopentanes
  • Excitatory Amino Acid Agents
  • Receptors, AMPA
  • Sulfonamides
  • glutamate receptor ionotropic, AMPA 4
  • propane-2-sulfonic acid (2-(4-iodophenyl)cyclopentyl)amide
  • Glutamic Acid