ABSTRACT-Structure-activity relationship of the chicken calcitonin gene-related peptide (cCGRP) was investigated and compared with human-a-CGRP (hCGRP) and rat CGRP (rCGRP) in the perfused mesenteric vascular beds of rats. In precontracted mesenteric vascular beds, cCGRP, hCGRP and rCGRP produced a concentration-dependent vasodilation. The vasodilator activities of cCGRP and rCGRP were equipotent and more potent than that of hCGRP. (Ala2,')cCGRP and (Des-l-Ala)-a-deamino cCGRP were 100 and 10-fold less potent than cCGRP, respectively. However, cCGRP curves of rCGRP to the right, but both peptides did not affect the maximum response and vasodilator responses to isoproterenol, these peptides being equipotent an tagonists (pA2 values: 7.6 and 7.4). In rat brain membrane preparations, cCGRP and its fragments and analogues, except for cCGRP , competed for specific binding sites with [125I]-hCGRP. These results suggest that cCGRP has a potent vasodilator activity for which the disulfide bridge at position 2 and 7 of cCGRP is an important site and that position 37 is necessary for the binding of the peptide to the receptor. Also, cCGRP [8 37] is a competitive CGRP-receptor antagonist.