PF-04455242

PF-04455242 is an orally bioavailable, blood-brain barrier-permeable κ-opioid receptor (KOR) inhibitor. PF-04455242 blocks in vivo effects induced by KOR and MOR agonists, and elicits KOR-independent outward currents in ventral tegmental area neurons. PF-04455242 promotes energy expenditure and activates the hypothalamic mTOR pathway. PF-04455242 attenuates stress-induced behavioral effects and produces antidepressant-like effects. PF-04455242 can be used in studies related to pain, depression, addictive disorders, and obesity induced by estrogen withdrawal^[1][2][3][4]. In Vitro:PF-04455242 (100 nM-1 μM) is a partial κ-opioid receptor antagonist with an IC₅₀ of 6.7 nM in dopamine neurons of the rat ventral tegmental area (VTA); at concentrations of 100 nM and 1 μM, it induces outward K⁺ currents in a subset of these neurons^[2].
PF-04455242 (60 minutes at room temperature) binds with high affinity (K_i = 3 nM) to human KOR stably expressed in CHO cells, and also binds with high affinity to rat KOR stably expressed in CHO cells (K_i = 21 nM) as well as mouse primary forebrain KOR (K_i = 22 nM)^[4].
PF-04455242 (treated at 30°C for 20 min; treated at 30°C for 30 min) acts as an antagonist of human KOR stably expressed in CHO cells, with higher potency (K_i = 1.2 nM) than that against human MOR (K_i = 10 nM)^[4]. In Vivo:PF-04455242 (3.4 nM/day; i.c.v.; continuous infusion; 7 days) reduces body weight gain in ovariectomized wild-type female mice, an effect independent of food intake, accompanied by upregulated expression of thermogenic markers in adipose tissue and activation of the hypothalamic mTOR signaling pathway^[3].
PF-04455242 (0.32-10 mg/kg; s.c.; single dose; 1 h before agonist administration) dose-dependently blocks the analgesic effects induced by KOR and MOR agonists in rats, and achieves dose-dependent, time-limited target binding to KOR and MOR in rat brains^[4].
PF-04455242 (0.32-10 mg/kg; s.c.n; single administration; 30 minutes prior to Spiradoline treatment) dose-dependently blocks Spiradoline (HY-106756)-induced elevation of plasma prolactin in rats, with an ED₅₀ of 2.3 mg/kg^[4].
PF-04455242 (0.32-10 mg/kg; s.c.; single administration; 1 h before testing) exhibits antidepressant-like efficacy in the mouse forced swim test, alleviates depression-like social defeat behavior in mice following repeated stress exposure, and prevents stress-induced reinstatement of extinguished cocaine-seeking behavior in mice^[4].