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.
Nur für Forschungszwecke. Wir verkaufen nicht an Patienten.
- CAS. Nr.: 1202647-54-8
- Formel: C21H28N2O2S
- Molecular Weight:372.52
-
Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
-
Biologische Aktivität
-
Chemical Information
- Protokoll
- Reinheit & Dokumentation
- Verweise
-
Help & FAQs
Alle Opioid Receptor Isoform-spezifische Produkte anzeigen
More
Biologische Aktivität
Beschreibung
IC50 & Target
[2]|
human κ-opioid receptor (hKOR) 3.0 nM (Ki) |
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 (Ki = 3 nM) to human KOR stably expressed in CHO cells, and also binds with high affinity to rat KOR stably expressed in CHO cells (Ki = 21 nM) as well as mouse primary forebrain KOR (Ki = 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 (Ki = 1.2 nM) than that against human MOR (Ki = 10 nM)[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
In Vivo
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].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
-
Animal Model:C57BL/6 wild-type (female, 8-10 weeks old, ovariectomy-induced obesity)[3]
-
Dosage:3.4 nM/day
-
Administration:i.c.v.; continuous infusion; 7 days
-
Result:Significantly reduced cumulative body weight gain compared to vehicle control (p < 0.05).
Showed no change in cumulative food intake.
Demonstrated a non-significant tendency toward reduced subcutaneous inguinal white adipose tissue depots (p = 0.07).
Significantly increased uncoupling protein 1-positive immunostaining in brown adipose tissue (p < 0.05) and subcutaneous inguinal white adipose tissue (p < 0.05) compared to vehicle control.
Significantly increased phosphorylated levels of mTOR (pmTOR) and phosphorylated S6 (pS6) in the medio-basal hypothalamic area (p < 0.01).
Showed a non-significant tendency toward increased phosphorylated p70S6K (pS6K) levels in the medio-basal hypothalamic area (p = 0.06).
-
Animal Model:Sprague-Dawley (male, 175-200 g); Sprague-Dawley (male, jugular vein cannulated, 300-400 g)[4]
-
Dosage:0.32, 1, 3.2, 10, 17.8, 32 mg/kg/0.1, 1, 3.2, 10, 32 mg/kg; 10 mg/kg (time-course)
-
Administration:s.c.; single dose; 1 hour before agonist administration
-
Result:Attenuated Spiradoline-induced tail-flick latency with an EC50 of 1.5 mg/kg.
Attenuated Morphine-induced tail-flick latency with an EC50 of 9.8 mg/kg.
Inhibited ex vivo [3H]CI977 binding to KORs with an ID50 of 2.0 mg/kg.
Inhibited ex vivo [3H]DAMGO binding to MORs with an ID50 of 8.6 mg/kg.
At 10 mg/kg, inhibited ex vivo [3H]CI977 binding by 60% at 15 minutes post-dose, reached maximal 82% inhibition at 30 minutes, maintained inhibition for 2 h, and showed no inhibition by 8 hours.
Inhibited in vivo [3H]PF-04767135 binding to KORs with an ID50 of 5.2 mg/kg.
-
Animal Model:Sprague-Dawley (male, jugular vein cannulated, 300-400 g)[4]
-
Dosage:0.32, 1, 3.2, 10 mg/kg
-
Administration:s.c.; single dose; 30 minutes before spiradoline
-
Result:Dose-dependently reduced Spiradoline-induced plasma prolactin elevation with an ED50 of 2.3 mg/kg.
At 3.2 or 10 mg/kg, had no effect on basal prolactin levels.
-
Animal Model:ICR (male, 25-30 g)[4]
-
Dosage:0.32, 1, 3.2 mg/kg/1, 3, 10 mg/kg
-
Administration:s.c.; single dose; 1 hour before testing/s.c.; daily; 3 days, 30 minutes before each social defeat trial
-
Result:Reduced immobility with a minimal effective dose of 3.2 mg/kg.
Dose-dependently reduced time spent in defeated postures: the 3 mg/kg dose produced a significant reduction on day 2, and all three doses produced significant reductions on day 3.
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date |
Phase
|
|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
-
CAS. Nr. 1202647-54-8
-
Molecular Weight 372.52
-
Formel C21H28N2O2S
-
SMILES
O=S(C1=CC=CC=C1C2=CC=C(CNCC(C)C)C=C2)(N3CCCC3)=O
-
Versand
Room temperature in continental US; may vary elsewhere.
-
Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Protokoll
-
Research Protocol for Endocrine Diseases
Endocrine diseases often arise from disrupted hormone production, hormone signaling, or target-tissue responsiveness; for diabetes-focused endocrine disease models, insulin signaling regulates glucose uptake, hepatic glucose output, lipid metabolism, and β-cell compensation. Type 2 diabetes develops through interacting defects in insulin resistance, β-cell dysfunction, adipose inflammation, hepatic glucose overproduction, altered incretin signaling, and ectopic lipid metabolism. A major unresolved question is whether endocrine dysfunction is driven primarily by target-tissue insulin resistance, intrinsic β-cell failure, immune/inflammatory stress, or combined multi-organ failure that differs by disease stage.
-
Research Protocol for Metabolic Diseases
AMP-activated protein kinase, AMPK, is a conserved cellular energy sensor that responds to reduced cellular energy status and coordinates metabolism by increasing ATP-generating catabolic pathways while suppressing ATP-consuming anabolic processes. In metabolic disease research, the AMPK pathway is experimentally relevant because it regulates hepatic lipid synthesis, fatty acid oxidation, glucose production, skeletal-muscle glucose disposal, mTORC1-linked biosynthesis, autophagy, mitochondrial homeostasis, and whole-body energy balance. The central pathway logic is that energy stress, metformin, exercise-like stimulation, or direct AMPK activators increase AMPKα Thr172 phosphorylation and downstream substrate phosphorylation, including ACC and RAPTOR. Phosphorylation of ACC suppresses lipogenesis and supports fatty acid oxidation, whereas phosphorylation of RAPTOR suppresses mTORC1 signaling and links cellular energy status to growth and protein synthesis control. The pathway is linked
Reinheit & Dokumentation
Verweise
[1]. Naganawa M, et al. Evaluation of the agonist PET radioligand [¹¹C]GR103545 to image kappa opioid receptor in humans: kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242. Neuroimage. 2014;99:69-79. [Content Brief]
[2]. Margolis EB, et al. Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology. PLoS One. 2020;15(12):e0232864. Published 2020 Dec 29. [Content Brief]
[3]. Romero-Picó A, et al. Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway. Int J Mol Sci. 2022;23(6):3118. Published 2022 Mar 14. [Content Brief]
[4]. Grimwood S, et al. Pharmacological characterization of 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for κ-opioid receptors. J Pharmacol Exp Ther. 2011;339(2):555-566. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
PF-04455242 Related Classifications
HY-15691 Related Classifications
Powered by Bioz