PF-06827443
PF-06827443 is an orally active M1 receptor positive allosteric modulator with an EC50 of 47 nM and a Ki of 16 nM, and a PDE11A4 inhibitor with an IC50 of 5.06 μM. PF-06827443 enhances the effects of acetylcholine. PF-06827443 crosses the blood-brain barrier, induces LTD in the prefrontal cortex, increases sEPSC frequency in layer V pyramidal cells, and increases striatal inositol monophosphate accumulation. PF-06827443 induces convulsions, impairs cognition, reduces stimulant-evoked locomotion, reverses Scopolamine (HY-N0296)-induced learning/memory deficits, and causes cholinergic adverse events and convulsions in rats and dogs. PF-06827443 can be used for research on schizophrenia and Alzheimer's disease.
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- CAS No.: 2115022-67-6
- 화학식: C24H24N2O4
- 분자량:404.46
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보관:
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]
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Biological Activity
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Chemical Information
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- 순도&문서
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Biological Activity
제품 설명
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| CHO | EC50 |
1900 nM
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Agonist activity against CHO cells stably expressing rat M1 assessed by intracellular calcium mobilization in the absence of an orthosteric muscarinic acetylcholine receptor agonist.
Agonist activity against CHO cells stably expressing rat M1 assessed by intracellular calcium mobilization in the absence of an orthosteric muscarinic acetylcholine receptor agonist.
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29683646 |
| CHO | EC50 |
36.1 nM
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Positive allosteric modulator activity against CHO cells stably expressing rat M1 assessed by intracellular calcium mobilization in the presence of an EC20 concentration of acetylcholine.
Positive allosteric modulator activity against CHO cells stably expressing rat M1 assessed by intracellular calcium mobilization in the presence of an EC20 concentration of acetylcholine.
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29683646 |
In Vitro
PF-06827443 (1-10 µM; 20 min) induces M1-dependent LTD of fEPSPs in mouse PFC slices[1].
PF-06827443 (10 µM; 5 min) increases sEPSC frequency in mouse PFC layer V pyramidal neurons[1].
PF-06827443 (40-7 nM) is a potent M1 PAM in a cell-based functional assay, with potency increasing from 40 nM to 7 nM as ACh concentration increases from ~EC9 to EC70[2].
PF-06827443 (8 μM) shows functional cooperativity with ACh in the human M1 β-arrestin assay (αβ/KB = 100) with a 1.4-fold β-arrestin bias[3].
PF-06827443 has an MDR efflux ratio of 11 in MDCK-MDR1 cells[3].
PF-06827443 (up to 3 μM) lacks agonist activity but produces PAM responses in rat CA1 hippocampal slices[3].
PF-06827443 produces PAM-dependent contractions in guinea pig ileum LMMP tissue[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
| Species | Dose | Route | CL | T1/2 | F | Cmax | AUC0-24 |
|---|---|---|---|---|---|---|---|
| Rat[3] | 0.5 mg/kg | i.v. | 2.4 mL/min/kg | / | / | / | / |
| Rat[3] | 2 mg/kg | p.o. | / | 6.7 h | 91 % | / | / |
| Dog[3] | 0.1 mg/kg | i.v. | 1.7 mL/min/kg | / | / | / | / |
| Dog[3] | 0.5 mg/kg | p.o. | / | 7.3 h | 65 % | / | / |
| Rat[3] | 1 mg/kg | p.o. | / | / | / | 73 nM | 1048 nM·h |
| Rat[3] | 5 mg/kg | p.o. | / | / | / | 313 nM | 4927 nM·h |
| Rat[3] | 15 mg/kg | p.o. | / | / | / | 1507 nM | 20609 nM·h |
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57Bl/6J (M1 receptor knockout and wildtype littermate controls)[1]
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Dosage:100 mg/kg
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Administration:i.p.; single administration
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Result:100 mg/kg PF-06827443 induced behavioral convulsions that reached stage 3 on the modified Racine scale in wildtype littermate mice; these convulsions were absent in M1 knockout mice.
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Animal Model:C57BL/6[3]
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Dosage:0.32, 1.0, and 3.2 mg/kg
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Administration:s.c.
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Result:Reduced stimulant-stimulated locomotor activity at 0.32, 1.0, and 3.2 mg/kg.
At 0.32 mg/kg, free brain concentration was 3.8 nM.
Exposure at 0.32 mg/kg was C_p,u 7.3 nM and C_b,u 3.8 nM; at 1.0 mg/kg was C_p,u 46 nM and C_b,u 14 nM; at 3.2 mg/kg was C_p,u 130 nM and C_b,u 32 nM.
Chemical Information
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CAS No. 2115022-67-6
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분자량 404.46
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화학식 C24H24N2O4
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SMILES
O=C1C2=CC(CC3=CC=C(C4=COC=N4)C=C3)=C(C)C=C2CN1[C@@H]5[C@H](COCC5)O
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선적
Room temperature in continental US; may vary elsewhere.
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보관
Please store the product under the recommended conditions in the Certificate of Analysis.
순도&문서
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
PF-06827443 Related Classifications
HY-120004 Related Classifications
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