Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist

Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardioton ic peptide, has a potential role for CGRP in diverse physiologic and pathop hysiologic 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-me thyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl) nitrobenzanilide], a selective nonpeptide antagonist of CGRP(1) receptor. SB-(+)-273779 inhibi ted I-125-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and h uman cloned CGRP1 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 IC50 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 resu lted in reduction in maximum CGRP-mediated adenylyl cyclase activity, sugge sting that this compound has irreversible binding characteristics. In addit ion, SB-(+)-273779 antagonized CGRP-mediated 1) stimulation of intracellula r Ca2+ in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of ins ulin-stimulated [C-14] deoxyglucose uptake in L6 cells, 3) vasodilation in rat pulmonary artery, and 4) decrease in blood pressure in anesthetized rat s. SB-(+)-273779 tested at 3 muM had no significant affinity for calcitonin , endothelin, angiotensin II, and alpha -adrenergic receptors under standar d ligand binding assays. SB-(+)-273779 also did not inhibit forskolin and p ituitary adenylate cyclase-activating polypeptide. These results suggest th at SB-(+)-273779 is a valuable tool for studying CGRP-mediated functional r esponses in complex biological systems.