RT Journal Article
SR Electronic
T1 Pharmacological Actions of a Novel, High-Affinity, and Selective Human Dopamine D<sub>3</sub> Receptor Antagonist,  SB-277011-A
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1154
OP 1165
VO 294
IS 3
A1 Reavill, Charlie
A1 Taylor, Stephen G.
A1 Wood, Martyn D.
A1 Ashmeade, Tracey
A1 Austin, Nigel E.
A1 Avenell, Kim Y.
A1 Boyfield, Izzy
A1 Branch, Clive L.
A1 Cilia, Jackie
A1 Coldwell, Martyn C.
A1 Hadley, Michael S.
A1 Hunter, A. Jackie
A1 Jeffrey, Phil
A1 Jewitt, Frances
A1 Johnson, Christopher N.
A1 Jones, Declan N. C.
A1 Medhurst, Andrew D.
A1 Middlemiss, Derek N.
A1 Nash, David J.
A1 Riley, Graham J.
A1 Routledge, Carol
A1 Stemp, Geoff
A1 Thewlis, Kevin M.
A1 Trail, Brenda
A1 Vong, Antonio K. K.
A1 Hagan, Jim J.
YR 2000
UL http://jpet.aspetjournals.org/content/294/3/1154.abstract
AB 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 D3 receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D3 or D2 long (hD3, hD2) receptors showed SB-277011-A to have high affinity for the hD3 receptor (pKi = 7.95) with 100-fold selectivity over the hD2 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 D3 or D2. In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD3 receptor (pKb = 8.3) and was 80-fold selective over hD2 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 D3 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 D3 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 D3 receptors may benefit the treatment of schizophrenia. The American Society for Pharmacology and Experimental Therapeutics