Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A

J Pharmacol Exp Ther. 2000 Sep;294(3):1154-65.


SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.

MeSH terms

  • Animals
  • Brain / metabolism
  • CHO Cells
  • Catalepsy / chemically induced
  • Cricetinae
  • Dopamine Antagonists / metabolism
  • Dopamine Antagonists / pharmacology*
  • Dopamine Antagonists / toxicity
  • Humans
  • Male
  • Microdialysis
  • Motor Activity / drug effects
  • Nitriles / metabolism
  • Nitriles / pharmacology*
  • Nitriles / toxicity
  • Prolactin / blood
  • Quinolines / metabolism
  • Quinolines / pharmacology*
  • Quinolines / toxicity
  • Radioligand Assay
  • Rats
  • Rats, Inbred Strains
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D3
  • Reflex, Startle / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrahydroisoquinolines*
  • Transfection


  • DRD3 protein, human
  • Dopamine Antagonists
  • Drd3 protein, rat
  • Nitriles
  • Quinolines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • SB 277011
  • Tetrahydroisoquinolines
  • Prolactin