K41498

K41498 is a highly selective CRF 2 receptor antagonist, with a K_i of 0.66 nM for human CRF2α receptor and a K_i of 0.62 nM for human CRF2β receptor. K41498 inhibits cAMP accumulation in cells expressing CRF2. K41498 antagonizes the hypotensive response induced by systemic administration of urocortin in conscious rats. K41498 can be radioiodinated without losing activity, and is applicable for autoradiographic studies of native CRF2 receptors in rat brain and peripheral tissues^[1][2]. In Vitro:K41498 (incubated at 22°C for 120 min) exhibits highly selective and high-affinity binding to hCRF₂α and hCRF₂β receptors in membrane homogenates of stably transfected HEK293 cells (K_i = 0.66 nM and 0.62 nM, respectively), which is significantly superior to its binding to hCRF₁ receptor^[1].
K41498 (10 μM in hCRF₁-expressing cells; 100 nM in hCRF₂α- and hCRF₂β-expressing cells; treated at 37°C for 10 min) is a potent, selective antagonist that inhibits cAMP accumulation in Svg-stimulated HEK293 cells expressing hCRF₂α and hCRF₂β. It exhibits only extremely low intrinsic agonist activity across all three receptor subtypes and shows weak activity at the hCRF₁ receptor^[1].
K41498 (100 nM, 10 min at 37°C for CRF₂α/CRF₂β cells; 10 μM, 10 min at 37°C for CRF₁ cells) potently inhibits sauvagine-induced cAMP accumulation in HEK293 cells expressing human CRF₂α and human CRF₂β at a concentration of 100 nM, shows only weak inhibitory effect on HEK293 cells expressing human CRF₁ at a concentration of 10 μM, and exhibits only extremely low intrinsic agonist activity in all three of the above-mentioned cell lines^[2]. In Vivo:K41498 (1 mg/kg; i.v.; single administration) specifically reduces the uptake of ¹²³I-K31440 in the small intestine of mice by 35%, confirming that it binds to peripheral CRF₂ receptors^[1].
K41498 (1.84 mg; i.v.; single administration, 10 minutes prior to urocortin administration) completely blocks the systemic urocortin-induced hypotensive response in conscious male Wistar-Kyoto rats, whereas K41498 (2.35 mg; i.c.v.; single administration, 10 minutes prior to urocortin administration) fails to block the pressor effect induced by urocortin^[2].