Characterization of Multisubstituted Corticotropin Releasing Factor (CRF) Peptide Antagonists (Astressins)

CRF mediates numerous stress-related endocrine, autonomic, metabolic, and behavioral responses. We present the synthesis and chemical and biological properties of astressin B analogues {cyclo(30–33)[d-Phe12,Nle21,38,CαMeLeu27,40,Glu30,Lys33]-acetyl-h/r-CRF(9–41)}. Out of 37 novel peptides, 17 (2, 4, 6–8, 10, 11, 16, 17, 27, 29, 30, 32–36) and 16 (3, 5, 9, 12–15, 18, 19, 22–26, 28, 31) had ki to CRF receptors in the high picomolar and low nanomole ranges, respectively. Peptides 1, 2, and 11 inhibited h/rCRF and urocortin 1-induced cAMP release from AtT20 and A7r5 cells. When Astressin C 2 was administered to adrenalectomized rats at 1.0 mg subcutaneously, it inhibited ACTH release for >7 d. Additional rat data based on the inhibitory effect of (2) on h/rCRF-induced stimulation of colonic secretory motor activity and urocortin 2-induced delayed gastric emptying also indicate a safe and long-lasting antagonistic effect. The overall properties of selected analogues may fulfill the criteria expected from clini...