title: Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist.
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 for these 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 (125)I-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and human cloned CGRP(1) receptor with K(i) values of 310 +/- 40 and 250 +/-15 nM, respectively. SB-(+)-273779 also inhibited CGRP (3 nM)-activated adenylyl cyclase in these systems with IC(50) values of 390 +/-10 nM (in SK-N-MC) and 210 +/-16 nM (recombinant human CGRP receptors). Prolonged treatment (>30 min) 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 Ca(2+) in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of insulin-stimulated [(14)C]deoxyglucose uptake in L6 cells, 3) vasodilation in rat pulmonary artery, and 4) decrease in blood pressure in anesthetized rats. SB-(+)-273779 tested at 3 microM 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.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA. Nambi_Aiyar-1@sbphrd.com
authors.forename: N
authors.initials: N
authors.lastname: Aiyar
authors.forename: R A
authors.initials: RA
authors.lastname: Daines
authors.forename: J
authors.initials: J
authors.lastname: Disa
authors.forename: P A
authors.initials: PA
authors.lastname: Chambers
authors.forename: C F
authors.initials: CF
authors.lastname: Sauermelch
authors.forename: M
authors.initials: M
authors.lastname: Quiniou
authors.forename: N
authors.initials: N
authors.lastname: Khandoudi
authors.forename: B
authors.initials: B
authors.lastname: Gout
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: R N
authors.initials: RN
authors.lastname: Willette
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000813:Anilides; C421684:SB-273779; D013844:Thiazoles; D015740:Calcitonin Gene-Related Peptide