Affinity of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives to the ion channel binding site of the NMDA receptor complex

Eur J Med Chem. 2006 Aug;41(8):1003-10. doi: 10.1016/j.ejmech.2006.03.005. Epub 2006 May 3.

Abstract

A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to the PCP binding site of the NMDA receptor complex. The (S)-configured tetrahydroisoquinoline derivative (S)-4 e x HCl bearing a 2-methylphenyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the derivatives with a K(i)-value of 0.0374 microM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times more potent than the corresponding (R)-enantiomer (R)-4 e x HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives is described.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ion Channels / chemistry
  • Ion Channels / drug effects*
  • Ion Channels / metabolism
  • Magnetic Resonance Spectroscopy
  • Radioligand Assay
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spectrophotometry, Infrared
  • Tetrahydroisoquinolines / metabolism
  • Tetrahydroisoquinolines / pharmacology*

Substances

  • Ion Channels
  • Receptors, N-Methyl-D-Aspartate
  • Tetrahydroisoquinolines
  • 1,2,3,4-tetrahydroisoquinoline