Abstract
The role of the N-terminal domains of corticotropin-releasing factor (CRF) and CRF-like peptides in receptor subtype selectivity, ligand affinity and biological potency was investigated. Therefore, human CRF 12–41, human URP 12–38 and antisauvagine-30 (aSvg) were N-terminally prolonged by consecutive addition of one or two amino acids. The peptides obtained were tested for their binding affinities to rat CRF 1 and murine CRF 2β receptor, and their capability to stimulate cAMP-release by HEK cells producing either receptor. It was observed that human CRF N-terminally truncated by eight residues was bound with high affinity to CRF 2 receptor ( K i =5.4 nM), whereas affinity for CRF 1 receptor was decreased ( K i =250 nM). A similar shift of affinity was found with sauvagine (Svg) analogs. Truncation of human URP analogs did not affect their preference for CRF 2β receptor, but reduced their affinity. Changes in affinity were positively correlated with changes in potency. These results indicated that CRF 1 receptor was more stringent in its structural requirements for ligands to exhibit high affinity binding than CRF 2β receptor.
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