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 k i 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 clinical candidates.