hCGRP8-37, a calcitonin gene-related peptide antagonist revealing calcitonin gene-related peptide receptor heterogeneity in brain and periphery.

The C-terminal fragment of human calcitonin gene-related peptide (CGRP), hCGRP8-37, fails to induce any biological activity in a variety of isolated tissues and behavioral assays even though it possesses nanomolar affinity for [125I]hCGRP alpha binding sites in the central nervous system and peripheral membrane preparations. However, hCGRP8-37 displays relatively potent, competitive antagonist properties toward the action of native hCGRP alpha in guinea pig atrial and ileal preparations and on the central nervous system-mediated inhibition of CGRP on food intake. On the contrary, in the rat vas deferens the antagonistic potency of hCGRP8-37 was much weaker and was ineffective against CGRP-induced hyperthermia after i.c.v. injection. Such evidence suggests the existence of at least two classes of CGRP receptors, the first (CGRP1) being sensitive to the antagonist properties of hCGRP8-37, whereas the second (CGRP2) is not. The use of hCGRP8-37 should greatly facilitate the characterization of the physiological roles of CGRP-like peptides, especially those which are mediated via the activation of CGRP1 receptors.