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

Citation
C. Reavill et al., Pharmacological actions of a novel, high-affinity, and selective human dopamine D-3 receptor antagonist, SB-277011-A, J PHARM EXP, 294(3), 2000, pp. 1154-1165
Citations number
42
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
00223565 → ACNP
Volume
294
Issue
3
Year of publication
2000
Pages
1154 - 1165
Database
ISI
SICI code
0022-3565(200009)294:3<1154:PAOANH>2.0.ZU;2-4
Abstract
SE-277011-A {trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethy l]cyclohexyl]-4-quinolinecarboxamide}, is a brain-penetrant, high-affinity, and selective dopamine D-3 receptor antagonist. Radioligand-binding experi ments 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 af finity 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 ce lls transfected with rat dopamine D-3 or D-2. In the microphysiometer funct ional assay, SB-277011-A antagonized quinpirole-induced increases in acidif ication in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and wa s 80-fold selective over hD(2) receptors. Central nervous system penetratio n studies showed that SB-277011-A readily entered the brain. In in vivo mic rodialysis studies, SB-277011-A (2.8 mg/kg p.o.) reversed the quinelorane-i nduced reduction of dopamine efflux in the nucleus accumbens but not striat um, 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 apomor phine- or quinpirole-treated rats, but did significantly reverse the prepul se 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 pla sma prolactin levels. Thus, dopamine D-3 receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor ant agonists. The effect of SB-277011-A on isolation-induced prepulse inhibitio n deficit suggests that blockade of dopamine D-3 receptors may benefit the treatment of schizophrenia.