Stressin1-A, a potent corticotropin releasing factor receptor 1 (CRF1)-selective peptide agonist.
The potencies and selectivity of peptide CRF antagonists is increased through structural constraints, suggesting that the resulting ligands assume distinct conformations when interacting with CRF1 and CRF2 receptors. To develop selective CRF receptor agonists, we have scanned the sequence -Gln-Ala-His-Ser-Asn-Arg- (residues 30-35 of [DPhe12,Nle21,38]Ac-hCRF4-41) with an i-(i+3) bridge consisting of the Glui-Xaa-Xbb-Lysi+3 scaffold, where residues i=30, 31, and 32. When i=31, stressin1-A, a potent CRF1 receptor-selective agonist was generated. In vitro, stressin1-A was equipotent to h/rCRF to release ACTH. Astressin1-A showed a low nanomolar affinity for CRF1 receptor (Ki=1.7 nM) and greater than 100-fold selectivity versus CRF2 receptor (Ki=222 nM). Stressin1-A released slightly less ACTH than oCRF in adult adrenal-intact male rats, with increased duration of action. Stressin1-A, injected intraperitoneally in rats, induced fecal pellet output (a CRF1 receptor-mediated response) and did not influence gastric emptying and blood pressure (CRF2 receptor-mediated responses).
Rivier
Jean
J
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, California 92037, USA. jrivier@salk.edu
Gulyas
Jozsef
J
Kunitake
Koichi
K
DiGruccio
Michael
M
Cantle
Jeffrey P
JP
Perrin
Marilyn H
MH
Donaldson
Cindy
C
Vaughan
Joan
J
Million
Mulugeta
M
Gourcerol
Guillaume
G
Adelson
David W
DW
Rivier
Catherine
C
Taché
Yvette
Y
Vale
Wylie
W
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003672:Defecation / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000166:cytology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists*; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
D010456:Peptides, Cyclic; D018019:Receptors, Corticotropin-Releasing Hormone; C519520:cyclo(31-34)(phenylalanyl(12)-norleucyl(21,28)-glutamyl(31)-lysyl(34))acetyl-corticotropin releasing factor (4-41); D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone