Stressin1-A, a potent corticotropin releasing factor receptor 1 (CRF1)-selective peptide agonist - PubMed (original) (raw)

. 2007 Apr 5;50(7):1668-74.

doi: 10.1021/jm0613875. Epub 2007 Mar 3.

Jozsef Gulyas, Koichi Kunitake, Michael DiGruccio, Jeffrey P Cantle, Marilyn H Perrin, Cindy Donaldson, Joan Vaughan, Mulugeta Million, Guillaume Gourcerol, David W Adelson, Catherine Rivier, Yvette Taché, Wylie Vale

Affiliations

Stressin1-A, a potent corticotropin releasing factor receptor 1 (CRF1)-selective peptide agonist

Jean Rivier et al. J Med Chem. 2007.

Abstract

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).

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Figures

Figure 1

Figure 1

Plasma ACTH levels in rats injected with the vehicle, 2 (oCRF), 6, 7 (stressin1-A) and 9. Each point represents the mean ± SEM of 6–7 animals. **, P<0.01 vs. vehicle.

Figure 2

Figure 2

A = Ucn 2 (hUcn 2) but not 7 (stressin1-A) injected ip decreased gastric emptying of a viscous noncaloric meal in conscious rats. Overnight fasted rats were injected ip with saline, Ucn 2 or 7 (stressin1-A), and 10 min later gavaged with the phenol red methylcellulose solution and 20 min later gastric emptying was monitored. Each column is the mean ± SE of 5–6 rats/group. *p < 0.05 compared with both vehicle and stressin1-A groups. B = 7 injected ip stimulated colonic motor function in conscious rats. Non fasted rats were injected ip with saline or 7 (stressin1-A, 10 μg/kg) and fecal pellet output and diarrhea in conscious rats was monitored. Each column represents the mean ± SE of 6 rat/group. The numbers on the bars are the number of rats with diarrhea over the total in a group. #P<0.05 vs. saline and stressin1-A; * P<0.05 vs. saline.

References

    1. Rivier JE, Gulyas J, Kirby D, Kunitake K, Donaldson C, Vaughan J, Perrin M, Koerber S, Martinez V, Taché Y, Rivier C, Vale W. Receptor-selective corticotropin releasing factor analogs. 31st Annual Meeting of the Society for Neuroscience; San Diego, CA. 2001. Session number 413.417.
    1. Gulyas J, Rivier C, Perrin M, Koerber SC, Sutton S, Corrigan A, Lahrichi SL, Craig AG, Vale WW, Rivier J. Potent, structurally constrained agonists and competitive antagonists of corticotropin releasing factor (CRF) Proc Natl Acad Sci USA. 1995;92:10575–10579. - PMC - PubMed
    1. Rivier J, Gulyas J, Kirby D, Low W, Perrin MH, Kunitake K, DiGruccio M, Vaughan J, Reubi JC, Waser B, Koerber SC, Martínez V, Wang LX, Taché Y, Vale W. Potent and long acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists. J Med Chem. 2002;45:4737–4747. - PubMed
    1. Rivier JE, Kirby DA, Lahrichi SL, Corrigan A, Vale WW, Rivier CL. Constrained corticotropin releasing factor (CRF) antagonists (Astressin analogues) with long duration of action in the rat. J Med Chem. 1999;42:3175–3182. - PubMed
    1. Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE. Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA. 2001;98:2843–2848. - PMC - PubMed

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