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

Abstract

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.

• Authors: C Reavill, S G Taylor, M D Wood, T Ashmeade, N E Austin, K Y Avenell, I Boyfield, C L Branch, J Cilia, M C Coldwell, M S Hadley, A J Hunter, P Jeffrey, F Jewitt, C N Johnson, D N Jones, A D Medhurst, D N Middlemiss, D J Nash, G J Riley, C Routledge, G Stemp, K M Thewlis, B Trail, A K Vong, J J Hagan
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 294 Issue 3 Pg. 1154-65 (Sep 2000) ISSN: 0022-3565 [Print] United States
• PMID: 10945872 (Publication Type: Journal Article)

Chemical References

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

Topics

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