Limitations in using peptide drugs to characterize calcitonin gene- related peptide receptors

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Calcitonin gene-related peptide (CGRP) is an endogenous vasodilator peptide that produces its effects by activation of CGRP1 and CGRP2 receptor subtypes. These receptor subtypes are characterized in functional studies using the agonist Cys(Acm)2,7-human-α-calcitonin gene-related peptide (Cys(ACM)2,7-h-α-CGRP), which activates CGRP2 receptors, and the antagonist h-αCGRP(8-37) which has a high affinity for CGRP1 receptors and a low affinity for CGRP2 receptors. Our aim was to identify factors that may limit the use of these drugs to characterize CGRP receptor subtypes. We studied CGRP receptors using isolated ring segments of pig coronary and basilar arteries studied in vitro. The affinity of the antagonist h-αCGRP(8- 37) for inhibiting h-αCGRP-induced relaxation of coronary arteries (log10 of the antagonist equilibrium dissociation constant = -5.33) was determined from Schild plots that had steep slopes. Therefore, we used capsaicin to investigate the role of endogenous CGRP in confounding affinity measurements for h-αCGRP(8-37). After capsaicin treatment, the slopes of the Schild plots were not different from one, and a higher affinity of h-CGRP(8-37) in blocking relaxation was obtained (log10 of the antagonist equilibrium dissociation constant = -6.01). We also investigated the agonist activity of the putative CGRP2 receptor selective agonist Cys(Acm)2,7-hαCGRP. We found that maximal relaxation of coronary arteries caused by Cys(Acm)2,7- h-αCGRP was dependent upon the level of contractile tone induced by KCl. We also determined the K(A) for Cys(Acm)2,7-h-αCGRP and found that the K(A) (817 nM) was not significantly different from the EC50 (503 nM) for this drug in causing relaxation, indicating that Cys(Acm)2,7-hαCGRP is a partial agonist. Because experimental conditions affect the actions of h- CGRP(8-37) and Cys(Acm)2,7-h-αCGRP, the conditions must be carefully controlled to reliably identify CGRP receptor subtypes.

Original languageEnglish (US)
Pages (from-to)1419-1426
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jun 1999

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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