Identification and synthesis of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to the alpha 2 delta-1 subunit of voltage gated calcium channel

Bioorg Med Chem Lett. 2004 May 17;14(10):2463-7. doi: 10.1016/j.bmcl.2004.03.008.

Abstract

We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha 2 delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC(50)=15 nM) and (S)-22 (IC(50)=30 nM). A potent and selective radioligand, [(3)H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.

MeSH terms

  • Amines / metabolism
  • Analgesics / chemical synthesis
  • Analgesics / pharmacology
  • Binding Sites
  • Calcium Channel Blockers / chemical synthesis*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / metabolism*
  • Cyclohexanecarboxylic Acids / metabolism
  • Gabapentin
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Phthalazines / chemical synthesis
  • Phthalazines / pharmacology*
  • Radioligand Assay
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Amines
  • Analgesics
  • Calcium Channel Blockers
  • Calcium Channels
  • Cyclohexanecarboxylic Acids
  • Ligands
  • Phthalazines
  • voltage gated calcium channel subunit Ca alpha2delta-1, human
  • gamma-Aminobutyric Acid
  • Gabapentin