I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor

J Pharmacol Exp Ther. 1997 Aug;282(2):1011-9.


NGD 94-1 was evaluated for selectivity and in vitro functional activity at the recombinant human D4.2 receptor stably expressed in Chinese hamster ovary cells. NGD 94-1 showed high affinity for the cloned human D4.2 receptor (Ki = 3.6 +/- 0.6 nM) and had greater than 600-fold selectivity for the D4.2 receptor subtype compared with a wide variety of monoamine or other neurotransmitter receptor or modulatory sites except for 5-HT1A and 5-HT3 receptors, in which NGD 94-1 was approximately 50- and 200-fold selective, respectively, for the D4.2 receptor. In measures of in vitro functional activity, NGD 94-1 showed an antagonist profile at the cloned human D4.2 receptor subtype. NGD 94-1 completely reversed the decrease in forskolin-stimulated cAMP levels produced by the dopamine receptor full agonist quinpirole. Furthermore, NGD 94-1 produced a complete reversal of GTPgamma35S binding induced by quinpirole, but was unable on its own to affect GTPgamma35S binding. These data suggest that NGD 94-1 functions as an antagonist rather than a full or partial agonist at the human D4.2 receptor. In addition, NGD 94-1 binding affinity at the D4.2 receptor subtype was unaffected by G-protein activation by GTP, consistent with the binding affinity seen for other antagonists at the D4 receptor. The binding of tritiated NGD 94-1 was saturable and of high affinity at cloned human D4.2 receptors. Furthermore, the binding of [3H]NGD 94-1 to cloned human D4.2 receptors expressed in Chinese hamster ovary cells displayed a pharmacological profile similar to that observed with the nonselective dopamine receptor ligand [3H]YM 09151-2. Saturation and pharmacological analyses of [3H]NGD 94-1 binding at cloned human D4.2, D4.4 and D4.7 receptor variants showed no difference between the three variants. NGD 94-1 is a novel, high-affinity, D4 receptor-selective antagonist. The clinical use of this subtype-specific compound should permit direct evaluation of the role of D4 receptors in psychiatric disorders.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Dopamine Antagonists / metabolism
  • Dopamine Antagonists / pharmacology*
  • Dopamine D2 Receptor Antagonists*
  • GTP-Binding Proteins / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Radioligand Assay
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D4
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Species Specificity
  • Tritium


  • DRD4 protein, human
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Imidazoles
  • Pyrimidines
  • Receptors, Dopamine D2
  • Recombinant Proteins
  • Tritium
  • Receptors, Dopamine D4
  • NGD 94-1
  • Guanosine Triphosphate
  • GTP-Binding Proteins