HTL-9936
Based on 1 Customer Validation
HTL-9936 is an orally active partial agonist of muscarinic M1 receptor. HTL-9936 has an EC50 of 32 nM for human M1 receptor and an EC50 of 224 nM for human M4 receptor. HTL-9936 activates Gq/11 coupling, promotes inositol phosphate accumulation, ERK1/2 phosphorylation, β-arrestin recruitment and receptor internalization. HTL-9936 can be used in the research of Alzheimer's disease and schizophrenia.
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- Pureza : 99.93%
- No. CAS: 1438242-59-1
- Fòrmula: C20H35N3O3
- Peso molecular:365.51
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Almacenamiento:
-20°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
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Actividad biológica
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Actividad biológica
Descripciòn
IC50 & Target
[4]|
mAChR1 32 nM (EC50) |
mAChR4 224 nM (EC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| CHO | EC50 |
168.8 nM
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Stimulation of intracellular calcium mobilization in CHO cells stably expressing human M1 receptors assessed by FLIPR assay at 37°C.
Stimulation of intracellular calcium mobilization in CHO cells stably expressing human M1 receptors assessed by FLIPR assay at 37°C.
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30276808 |
| CHO | EC50 |
1161 nM
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Stimulation of pERK 1/2 (Thr202/Tyr204) signalling in CHO cells stably expressing human M1 receptors, measured using an HTRF kit after overnight serum starvation and 10 min agonist stimulation at 37°C.
Stimulation of pERK 1/2 (Thr202/Tyr204) signalling in CHO cells stably expressing human M1 receptors, measured using an HTRF kit after overnight serum starvation and 10 min agonist stimulation at 37°C.
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30276808 |
| CHO | EC50 |
631 nM
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Agonist activity measured via inositol phosphate (IP1) accumulation assay in CHO Flp-In cells stably expressing human M1 muscarinic acetylcholine receptor, incubated at 37°C for 45 min, with FRET signals normalized to acetylcholine-induced maximum response.
Agonist activity measured via inositol phosphate (IP1) accumulation assay in CHO Flp-In cells stably expressing human M1 muscarinic acetylcholine receptor, incubated at 37°C for 45 min, with FRET signals normalized to acetylcholine-induced maximum response.
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34822784 |
| CHO-K1 | EC50 |
32 nM
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Full agonist activity measured via pERK1/2 phosphorylation assay in CHO-K1 cells stably expressing human M1 muscarinic acetylcholine receptor, serum-starved overnight then stimulated for 5 min at 37°C, with phosphorylated ERK1/2 levels measured via AlphaScreen Surefire assay and normalized to acetylcholine-induced maximum response.
Full agonist activity measured via pERK1/2 phosphorylation assay in CHO-K1 cells stably expressing human M1 muscarinic acetylcholine receptor, serum-starved overnight then stimulated for 5 min at 37°C, with phosphorylated ERK1/2 levels measured via AlphaScreen Surefire assay and normalized to acetylcholine-induced maximum response.
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34822784 |
| CHO-K1 | EC50 |
398 nM
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Partial agonist activity measured via pERK1/2 phosphorylation assay in CHO-K1 cells stably expressing human M4 muscarinic acetylcholine receptor, serum-starved overnight then stimulated for 5 min at 37°C, with phosphorylated ERK1/2 levels measured via AlphaScreen Surefire assay and normalized to acetylcholine-induced maximum response.
Partial agonist activity measured via pERK1/2 phosphorylation assay in CHO-K1 cells stably expressing human M4 muscarinic acetylcholine receptor, serum-starved overnight then stimulated for 5 min at 37°C, with phosphorylated ERK1/2 levels measured via AlphaScreen Surefire assay and normalized to acetylcholine-induced maximum response.
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34822784 |
| CHO | EC50 |
79 nM
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Full agonist activity measured via label-free dynamic mass redistribution (DMR) assay in CHO cells expressing human M1 muscarinic acetylcholine receptor.
Full agonist activity measured via label-free dynamic mass redistribution (DMR) assay in CHO cells expressing human M1 muscarinic acetylcholine receptor.
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34822784 |
In Vitro
HTL-9936 (30 min) acts as a low-potency but high-efficacy partial agonist at native rat cortical M1 receptors, with an EC50 of 2-2.7 μM[1].
HTL-9936 (2 h) binds to human recombinant M1 receptor, with a Ki value of 9093 nM[1].
HTL-9936 potently stimulates calcium mobilization in CHO cells expressing human M1 receptors, with an EC50 of 168.8 nM[1].
HTL-9936 (10 min) stimulates the pERK signaling pathway in CHO cells expressing human M1 receptors, with an EC50 of 1161 nM[1].
HTL-9936 potently activates recombinant human M1 receptors (EC50 = 32 nM) and human M4 receptors (EC50 = 224 nM), but shows no activity against human M2 and M3 receptors[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
| Species | Dose | Route | Cmax |
|---|---|---|---|
| Rat[6] | 3, 10, 30, 100 mg/kg | p.o. | 6400 ng/mL |
In Vivo
HTL-9936 (intravenous injection; 2-hour infusion) causes a transient, dose-dependent increase in blood pressure in purebred male Beagle dogs during intravenous infusion[6].
HTL-9936 (3 mg/kg) reverses scopolamine (HY-N0296)-induced cognitive impairment in rats, with an ED50 of 3 mg/kg[4].
HTL-9936 (10-100 mg/kg; i.p.) dose-dependently restores contextual fear conditioning impaired by Scopolamine in male C57BL/6J mice[6].
HTL-9936 (3-30 mg/kg; p.o.) dose-dependently reverses scopolamine-induced passive avoidance deficits in adult male Wistar rats[6].
HTL-9936 (3 mg/kg; p.o.) exerts an additive partial reversal effect on Scopolamine-induced passive avoidance deficits in adult male Wistar rats when combined with a sub-effective dose of Donepezil (HY-14566)[6].
HTL-9936 (10 mg/kg; p.o.) improves working memory in the rat novel object recognition model.
HTL-9936 (30 mg/kg; i.p.) improves fear conditioning learning and memory deficits in Tg37 mice, a prion disease model[6].
HTL-9936 (0.3-1 mg/kg, subcutaneous injection, once daily for 10 consecutive days) significantly improves visuospatial working memory in aged Beagle dogs[6].
HTL-9936 (0.3-3 mg/kg; subcutaneous injection) increases the δ wave power in resting-state electroencephalograms of adult male cynomolgus monkeys[6].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J (male, 8-12 weeks, scopolamine-induced contextual fear conditioning deficit model)[6]
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Dosage:10, 30, 100 mg/kg
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Administration:i.p.
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Result:Dose-dependently restored contextual-dependent fear learning and memory impaired by Scopolamine.
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Animal Model:Wistar (male, ~11 weeks, scopolamine-induced passive avoidance deficit model)[6]
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Dosage:3, 10, 30 mg/kg
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Administration:p.o.
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Result:Dose-dependently reversed Scopolamine-induced amnesia.
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Animal Model:Wistar (male, ~11 weeks, scopolamine-induced passive avoidance deficit model with sub-effective donepezil)[6]
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Dosage:3 mg/kg
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Administration:p.o.
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Result:Produced a significant partial reversal of Scopolamine-induced deficits when combined with sub-effective Donepezil, consistent with an additive effect.
Reached an estimated unbound brain concentration of 79 nM.
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Animal Model:Wistar (male, ~11 weeks, novel object recognition working memory model)[6]
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Dosage:3, 10, 30 mg/kg
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Administration:p.o.
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Result:Improved working memory at 10 mg/kg.
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Animal Model:Tg37 hemizygous (male, 9 weeks post-inoculation with Rocky Mountain Laboratory prions, prion-induced fear conditioning deficit model)[6]
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Dosage:30 mg/kg
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Administration:i.p.
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Result:Improved hippocampal-dependent contextual learning and memory, with treated mice showing 34% immobility compared to 13% in vehicle-treated mice.
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Animal Model:Beagle (male and female, > 8 years, delayed non-matching to position visual-spatial working memory model)[6]
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Dosage:0.3, 1, 2 mg/kg
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Administration:s.c.; once daily for 10 days
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Result:Significantly improved visual-spatial memory at 0.3 mg/kg and 1 mg/kg.
Produced an effect equivalent to that of Donepezil (1.5 mg/kg, p.o.) at 1 mg/kg.
Reached measured CSF concentrations of 13 nM at 0.3 mg/kg, 48 nM at 1 mg/kg, and 128 nM at 2 mg/kg.
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Animal Model:(male, 8-10 kg, 12-15 years old, quantitative EEG resting state network firing assessment)[6]
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Dosage:0.3, 3 mg/kg
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Administration:s.c.
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Result:Increased delta power in resting state EEG.
Reached predicted unbound brain concentrations of 20 nM at 0.3 mg/kg and 198 nM at 3 mg/kg.
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Animal Model:Wistar (male, 220-300 g, cardiovascular safety pharmacology assessment)[6]
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Dosage:3, 10, 30, 100 mg/kg
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Administration:p.o.
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Result:Caused a dose-dependent increase in heart rate and mean arterial blood pressure averaged over the 5-hour post-dose period, with no significant effects at 3 mg/kg.
Produced transient effects that returned to baseline as reagent exposure declined.
Chemical Information
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No. CAS 1438242-59-1
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Appearance Solid-liquid mixture
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Peso molecular 365.51
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Fòrmula C20H35N3O3
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Color Off-white to light yellow
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SMILES
CC1(CCC1)NC(C2CCN([C@@H]3CCN(CCC3)C(OCC)=O)CC2)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
-20°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
Pureza y Documentación
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Ficha de datos (287 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Instrucciones de manejo (2659 KB)
Referencias
[3]. Nguyen HTM, et al. Opportunities and challenges for the development of M muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits. British journal of pharmacology. 2024 Jul;181(14):2114-2142. [Content Brief]
[4]. Felder CC, et al. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases. Neuropharmacology. 2018 Jul 01;136(Pt C):449-458. [Content Brief]
[5]. Johnson CR, et al. Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders. Biomedicines. 2022 Feb 07;10(2):398. [Content Brief]
[6]. Brown AJH, et al. From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease. Cell. 2021 Nov 24;184(24):5886-5901.e22. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
HTL-9936 Related Classifications
HY-148961 Related Classifications
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