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.
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- CAS No.: 1202647-54-8
- Formula: C21H28N2O2S
- Molecular Weight:372.52
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Help & FAQs
All Opioid Receptor Isoforms
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Biological Activity
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human κ-opioid receptor (hKOR) 3.0 nM (Ki) |
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.
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.
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Animal Model:C57BL/6 wild-type (female, 8-10 weeks old, ovariectomy-induced obesity)[3]
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Dosage:3.4 nM/day
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Administration:i.c.v.; continuous infusion; 7 days
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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).
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Animal Model:Sprague-Dawley (male, 175-200 g); Sprague-Dawley (male, jugular vein cannulated, 300-400 g)[4]
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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)
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Administration:s.c.; single dose; 1 hour before agonist administration
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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.
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Animal Model:Sprague-Dawley (male, jugular vein cannulated, 300-400 g)[4]
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Dosage:0.32, 1, 3.2, 10 mg/kg
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Administration:s.c.; single dose; 30 minutes before spiradoline
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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.
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Animal Model:ICR (male, 25-30 g)[4]
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Dosage:0.32, 1, 3.2 mg/kg/1, 3, 10 mg/kg
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Administration:s.c.; single dose; 1 hour before testing/s.c.; daily; 3 days, 30 minutes before each social defeat trial
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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.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 1202647-54-8
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Molecular Weight 372.52
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Formula C21H28N2O2S
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SMILES
O=S(C1=CC=CC=C1C2=CC=C(CNCC(C)C)C=C2)(N3CCCC3)=O
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
[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
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
PF-04455242 Related Classifications
HY-15691 Related Classifications
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