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Titolo:
Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist
Autore:
Aiyar, N; Daines, RA; Disa, J; Chambers, PA; Sauermelch, VF; Quiniou, MJ; Khandoudi, N; Gout, B; Douglas, SA; Willette, RN;
Indirizzi:
SmithKline Beecham Pharmaceut, Dept Cardiovasc Pharmacol, King Of Prussia,PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 a,PA 19406 USA SmithKline Beecham Pharmaceut, Dept Med Chem, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA SmithKline Beecham Pharmaceut, Unite Rech, St Gregoire, France SmithKline Beecham Pharmaceut St Gregoire France h, St Gregoire, France
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 296, anno: 2001,
pagine: 768 - 775
SICI:
0022-3565(200103)296:3<768:POSANC>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
BINDING-SITES; CGRP; AMYLIN; ARTERY; MICROVASCULATURE; ADRENOMEDULLIN; ENDOTHELIUM; RELAXATION; TISSUES; BRAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Aiyar, N SmithKline Beecham Pharmaceut, Dept Cardiovasc Pharmacol, UW2510,709 Swedeland Rd,Box 1539, King Of Prussia, PA 19406 USA SmithKline BeechamPharmaceut UW2510,709 Swedeland Rd,Box 1539 King Of Prussia PA USA 19406
Citazione:
N. Aiyar et al., "Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist", J PHARM EXP, 296(3), 2001, pp. 768-775

Abstract

Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardiotonic peptide, has a potential role for CGRP in diverse physiologic and pathophysiologic situations such as congestive heart failure, diabetes, migraine, and neurogenic inflammation. Although a peptide CGRP receptor antagonist,CGRP(8-37), is available, its utility presents significant limitations forthese indications. Here, we describe the properties of SB-(+)- 273779 [N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl) nitrobenzanilide],a selective nonpeptide antagonist of CGRP(1) receptor. SB-(+)-273779 inhibited I-125-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and human cloned CGRP1 receptor with K-i values of 310 +/- 40 and 250 +/- 15 nM, respectively. SB-(+)-273779 also inhibited CGRP (3 nM)-activated adenylylcyclase in these systems with IC50 values of 390 +/-10 nM (in SK-N-MC) and210 +/- 16 nM (recombinant human CGRP receptors). Prolonged treatment (>30min) of SK-N-MC cells with SB-(+)-273779 followed by extensive washing resulted in reduction in maximum CGRP-mediated adenylyl cyclase activity, suggesting that this compound has irreversible binding characteristics. In addition, SB-(+)-273779 antagonized CGRP-mediated 1) stimulation of intracellular Ca2+ in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of insulin-stimulated [C-14] deoxyglucose uptake in L6 cells, 3) vasodilation inrat pulmonary artery, and 4) decrease in blood pressure in anesthetized rats. SB-(+)-273779 tested at 3 muM had no significant affinity for calcitonin, endothelin, angiotensin II, and alpha -adrenergic receptors under standard ligand binding assays. SB-(+)-273779 also did not inhibit forskolin and pituitary adenylate cyclase-activating polypeptide. These results suggest that SB-(+)-273779 is a valuable tool for studying CGRP-mediated functional responses in complex biological systems.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/20 alle ore 06:28:25