title: Characterization of Multisubstituted Corticotropin Releasing Factor (CRF) Peptide Antagonists (Astressins).
abstract: 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-Phe(12),Nle(21,38),C(α)MeLeu(27,40),Glu(30),Lys(33)]-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.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.affiliation: Department of Medicine, CURE/Digestive Diseases Center, Digestive Diseases Division, University of California at Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, United States.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Gulyas
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Manoj
authors.initials: M
authors.lastname: Samant
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Marilyn H
authors.initials: MH
authors.lastname: Perrin
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Kathy
authors.initials: K
authors.lastname: Lewis
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Charleen
authors.initials: C
authors.lastname: Miller
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Joan
authors.initials: J
authors.lastname: Vaughan
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Donaldson
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischer
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: William
authors.initials: W
authors.lastname: Low
authors.affiliation: Department of Medicine, CURE/Digestive Diseases Center, Digestive Diseases Division, University of California at Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, United States.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Yakabi
authors.affiliation: Department of Medicine, CURE/Digestive Diseases Center, Digestive Diseases Division, University of California at Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, United States.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Karasawa
authors.affiliation: Department of Medicine, CURE/Digestive Diseases Center, Digestive Diseases Division, University of California at Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, United States.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Taché
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rivier
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies , 10010 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D054832:Urocortins / Q000037:antagonists & inhibitors
chemical_list: D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C000607145:Ucn protein, rat; D054832:Urocortins; C120841:astressin B; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP