Structure-activity relationships in calcitonin gene-related peptide: cyclic AMP response in a preosteoblast cell line (KS-4).
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.
Thiebaud
D
D
St. Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
Akatsu
T
T
Yamashita
T
T
Suda
T
T
Noda
T
T
Martin
R E
RE
Fletcher
A E
AE
Martin
T J
TJ
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D013329:Structure-Activity Relationship
D010710:Phosphates; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium