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
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.