Astressin 2B

Astressin 2B is a blood-brain barrier-impermeable, highly selective CRFR2 antagonist (rCRF2, IC₅₀ = 0.57 nM). Astressin 2B blocks the protective effects mediated by CRFR2, thereby exacerbating Indomethacin (HY-14397)-induced hemorrhagic intestinal injury in rats. Astressin 2B reverses the protective effects of Urocortin 1 against intestinal hypermotility, bacterial invasion and upregulation of inflammatory mediators. Astressin 2B also blocks the anxiogenic effect of Urocortin 2 and attenuates stress-induced anxiety-related behaviors. In a C. difficile toxin A-mediated enteritis model, Astressin 2B mimics the phenotype of CRFR2-deficient mice, significantly exacerbating intestinal epithelial damage, edema, neutrophil migration and the expression of multiple proinflammatory cytokines. Astressin 2B is a valuable tool molecule for investigating the intestinal protective mechanisms of CRFR2^{[1][2][3][4][5][6][7]}. In Vitro: Astressin 2B potently binds to CRF₂ receptors in rat choroid plexus and blood vessels (IC₅₀=0.57 nM)^[1].
Astressin 2B binds to the cloned human CRF₂ (a) receptor expressed in the cell membrane of CHO-K1 cells with extremely high affinity (K_i=0.49 nM)^[2].
Astressin 2B binds to endogenous rat CRF₂ (b) receptors in A7r5 cell homogenates with extremely high affinity (K_i=0.17 nM)^[2].
Astressin 2B (1-100 nM; 15 min) concentration-dependently inhibits Urocortin III (HY-P1858)-mediated relaxation of tracheal smooth muscle in in vitro relaxation assays of methacholine (HY-A0083)-precontracted mouse tracheal smooth muscle, with an IC₅₀ of approximately 3 nM^[5]. In Vivo: Astressin 2B (3-100 µg/kg; i.p., s.c.) dose-dependently and completely reverses urocortin-induced delayed gastric emptying in mice, and exerts this effect at a dose of 10 µg/kg (i.p.)^[1].
Following septal administration via bilateral septal perfusion of Astressin 2B (24-192 pmol), doses of 24 pmol and 96 pmol block the stress-dependent anxiogenic effect of urocortin 2 in the septum, while the 192 pmol dose reduces stress-induced anxiety in both vehicle-treated and urocortin 2-treated mice^[3].
Astressin 2B (60 μg/kg; i.v.) reverses the CRFR2-mediated protective effects of Ucn I, including attenuation of injury, inhibition of MPO activity, reduction of intestinal bacterial invasion, downregulation of iNOS expression, and alleviation of intestinal hypermotility^[4].
Astressin-2B (60 μg/kg; i.v.; single dose 10 minutes before indomethacin administration; single dose 10 minutes before Urocortin I administration in reversal/motility studies) exacerbates indomethacin-induced small intestinal lesions and completely reverses all Urocortin I-mediated protective effects against indomethacin-induced intestinal damage, inflammation, bacterial invasion, and hypermotility, confirming these protective effects are mediated via CRFR2^[6].
Astressin 2B (3-300 μg/kg; i.p.; single dose 30 minutes pre-toxin A exposure) dose-dependently reduces intestinal fluid secretion and inhibits neutrophil infiltration, MPO activity, and proinflammatory chemokine production in a mouse model of Clostridium difficile toxin A-induced intestinal inflammation^[7].