Corticotropin-releasing factor peptide antagonists: Design, characterization and potential clinical relevance

• CRFs are mediators of gut, heart, skin, immune system and CNS homeostasis.
• First antagonist α-helical CRF(9–41) is potent in the brain, less though in the periphery.
• CRF antagonists will likely play a major role in stress-related diseases.
• Astressin2-B was designed to be a CRFR2 selective long acting antagonist.
• Stressin1 was designed to be a CRFR1selective agonist.

Elusive for more than half a century, corticotropin-releasing factor (CRF) was finally isolated and characterized in 1981 from ovine hypothalami and shortly thereafter, from rat brains. Thirty years later, much has been learned about the function and localization of CRF and related family members (Urocortins 1, 2 and 3) and their 2 receptors, CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2). Here, we report the stepwise development of peptide CRF agonists and antagonists, which led to the CRFR1 agonist Stressin1; the long-acting antagonists Astressin2-B which is specific for CRFR2; and Astressin B, which binds to both CRFR1 and CRFR2.This analog has potential for the treatment of CRF-dependent diseases in the periphery, such as irritable bowel syndrome.