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Titolo:
Pharmacological actions of a novel, high-affinity, and selective human dopamine D-3 receptor antagonist, SB-277011-A
Autore:
Reavill, C; Taylor, SG; Wood, MD; Ashmeade, T; Austin, NE; Avenell, KY; Boyfield, I; Branch, CL; Cilia, J; Coldwell, MC; Hadley, MS; Hunter, AJ; Jeffrey, P; Jewitt, F; Johnson, CN; Jones, DNC; Medhurst, AD; Middlemiss, DN; Nash, DJ; Riley, GJ; Routledge, C; Stemp, G; Thewlis, KM; Trail, B; Vong, AKK; Hagan, JJ;
Indirizzi:
SmithKline Beecham Pharmaceut, Dept Neurosci Res, Harlow CM19 5AD, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AD ssex, England SmithKline Beecham Pharmaceut, Dept Discovery Chem, Harlow CM19 5AD, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AD ssex, England SmithKline Beecham Pharmaceut, Dept Drug Metab & Pharmacokinet, Harlow CM19 5AD, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AD ssex, England
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 294, anno: 2000,
pagine: 1154 - 1165
SICI:
0022-3565(200009)294:3<1154:PAOANH>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
PREPULSE INHIBITION; ANTIPSYCHOTIC-DRUGS; HUMAN FOREBRAIN; MESSENGER-RNA; D2 RECEPTORS; MUTANT MICE; HUMAN BRAIN; IN-VIVO; D3; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Reavill, C SmithKline Beecham Pharmaceut, Neurosci Res, New Frontiers Sci Pk,3rd Ave,Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut New Frontiers Sci Pk,3rd Ave Harlow Essex England CM19 5AW
Citazione:
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

Abstract

SE-277011-A {trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide}, is a brain-penetrant, high-affinity, and selective dopamine D-3 receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamineD-3 or D-2 long (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity 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 cells transfected with rat dopamine D-3 or D-2. In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) 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 D-3 receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affectspontaneous 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 D-3 receptor blockade produces few ofthe 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 D-3 receptors may benefit thetreatment of schizophrenia.

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Documento generato il 27/01/20 alle ore 13:50:26