Peptidic Antagonist to CRF2 Receptor–Astressin 2B

2018-08-18

Introduction 

Astressin 2B is a peptidic antagonist to CRF2 (corticotrophin-releasing factor 2) receptor with structure of cyclo (31-34) [DPhe11, His12, CαMeLeu13,39, Nle17, Glu31, Lys34] Ac-Sauvagine(8-40). CRF2 selectivity can be induced to different extents by the introduction of the Glu32-Lys35 lactam bridge in hCRF(12-24) or the introduction of the corresponding Glu31-Lys34 lactam bridge in sauvagine(8-40) and sauvagine(11-40). This investigation ultimately led to the discovery of Astressin 2B, a potent and long-acting CRF2 selective antagonist as determined in several bioassays.

Biological Activity

CRF is recognized as a central mediator of the body's ability to respond to stress, which was initially isolated from ovine hypothalamus and characterized as a 41-amino acid peptide in 1981. CRF plays a major role in the maintenance or restoration of homeostasis by stimulating the activity of the hypothalamic-pituitary-adrenal (HPA) axis. It also acts within the central nervous system to control immune, reproductive, gastrointestinal/ ingestive, and cardiovascular functions, as well as catecholamine release, drug withdrawal, behavior, and mood and anxiety. Astressin 2B can potently and selectively block the CRF2 receptor (IC50 values are 1.3 and > 500 nM for CRF2 and CRF1 respectively).

Function

As a peptide CRF2 antagonist, Astressin 2B would not cross the blood-brain barrier, and injected centrally, it would have effects not seen with the administration of CRH (corticotropin releasing hormone) antibodies because of its smaller molecular weights and increased ability to diffuse. As such, it is also an ideal tool for mechanistic studies aimed at distinguishing pharmacological from physiological effects and, pharmacologically, for proof of concept in the search for possible clinical indications. In the rat model, the role of CRF2 in stress-induced suppression of the GnRH pulse generator has been confirmed by blockade of not only restraint but also hypoglycaemia and LPS stress-induced suppression of pulsatile LH secretion by central administration of the Astressin 2B, and it also pulsatile LH secretion suppressed by central administration of orexin A.

References

1. J. Rivier, J. Gulyas, D. Kirby, W. Low, M. H. Perrin, K. Kunitake, M. DiGruccio, J. Vaughan, J. C. Reubi, B. Waser, S. C. Koerber, V. Martinez, L. Wang, Y. Tache, W. Vale. Potent and Long-Acting Corticotropin Releasing Factor (CRF) Receptor 2 Selective Peptide Competitive Antagonists. J. Med. Chem. 2002, 45, 4737-4747.

2. Rivier CL, Grigoriadis DE, Rivier JE. Role of Corticotropin-Releasing Factor Receptors Type 1 and 2 in Modulating the Rat Adrenocorticotropin Response to Stressors. Endocrinology, 2003, 144 (6), 2396.

3. X.F. Li, A.M.I. Knox, K.T. O'Byrne. Corticotrophin-releasing factor and stress-induced inhibition of the gonadotrophin-releasing hormone pulse generator in the female. Brain Research. 2010, 1364, 153-163.

4. Shaaban A. Mousa, C.P. Bopaiah, Christoph Stein, Michael Schäfer. Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain. Pain, 2003, 106, 297-307.

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