Structure‐activity relationships in calcitonin gene‐related peptide: Cyclic AMP response in a preosteoblast cell line (ks‐4)

Abstract

Synthetic analogs of chicken and human CGRP were used to define structure‐function relationships in a murine osteoblast precursor cell line, KS‐4, that exhibits a substantial cyclic AMP response to CGRP but no response to calcitonin. Human CGRP had 40% of the activity of chicken CGRP, but [Asp‐14]‐human CGRP was equipotent with chicken CGRP. Similar observations were made previously for calcium‐ and phosphate‐lowering effects. Des‐1‐Ala, deamino CGRP compounds of both human and chicken origin were three‐fold more potent than the respective native CGRPs. The [4‐F‐Phe)‐37]‐chicken CGRP analog had a four‐fold enhanced activity. In all of the 13 analogs either truncated amino‐terminally or missing the (2–7)‐disulfide bridge, biologic activity was greatly reduced (0.1% of chicken CGRP), as it was in chicken CGRP‐(1–36)‐OH, which lacks the C‐terminal amino acid. The same analog has been shown to retain a hypocalcemic effect, which is most likely mediated through calcitonin receptors. In confirmation of their antagonistic effect reported in liver, analogs that lack the N‐terminal ring structure exhibited significant antagonistic activity. The data illustrate the specificity of CGRP receptors in promoting cyclic AMP formation in osteoblast‐like cells. Such CGRP analogs will be useful in investigating structure‐function relationships of CGRP. Copyright © 1991 ASBMR