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 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.
Footnotes
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Send reprint requests to: Dr. Charlie Reavill, Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Ave., Harlow, Essex CM19 5AW, UK. E-mail:Charlie_Reavill-1{at}SBPHRD.COM
- Abbreviations:
- hD2
- human dopamine D2
- CHO
- Chinese hamster ovary
- rD2
- rat dopamine D2
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
- RT-PCR
- reverse transcription-polymerase chain reaction
- PPI
- prepulse inhibition
- DMSO
- dimethyl sulfoxide
- CNS
- central nervous system
- LC/MS/MS
- liquid chromatography/mass spectrometry/mass spectrometry
- ISI
- interstimulus interval
- Received February 18, 2000.
- Accepted May 16, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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