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Vol. 294, Issue 3, 1154-1165, September 2000

Pharmacological Actions of a Novel, High-Affinity, and Selective Human Dopamine D3 Receptor Antagonist, SB-277011-A

Charlie Reavill , Stephen G. Taylor, Martyn D. Wood, Tracey Ashmeade, Nigel E. Austin, Kim Y. Avenell, Izzy Boyfield, Clive L. Branch, Jackie Cilia, Martyn C. Coldwell, Michael S. Hadley, A. Jackie Hunter, Phil Jeffrey, Frances Jewitt, Christopher N. Johnson, Declan N. C. Jones, Andrew D. Medhurst, Derek N. Middlemiss, David J. Nash, Graham J. Riley, Carol Routledge, Geoff Stemp, Kevin M. Thewlis, Brenda Trail, Antonio K. K. Vong and Jim J. Hagan

Departments of Neuroscience Research (C.R., S.G.T., M.D.W., T.A., K.Y.A., I.B., J.C., M.C.C., A.J.H., F.J., D.N.C.J., A.D.M., D.N.M., G.J.R., C.R., B.T., J.J.H.), Discovery Chemistry (C.L.B., M.S.H., C.N.J., D.J.N., G.S., K.M.T., A.K.K.V.), and Drug Metabolism and Pharmacokinetics (N.E.A., P.J.), SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, United Kingdom

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.

0022-3565/00/2943-1154$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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