| Targets |
Milameline hydroiodide targets muscarinic acetylcholine receptors (mAChRs), which are G protein-coupled receptors (GPCRs) expressed throughout the central and peripheral nervous systems. It acts as a partial agonist across multiple subtypes (M1-M4) with relatively balanced affinity (IC50 approximately 1.1-1.9 uM). It has a higher affinity for [3H]CMD binding sites (IC50 = 20 nM) than for [3H]QNB sites (IC50 = 3059 nM), indicating complex binding interactions.
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| ln Vitro |
In vitro, Milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist. It demonstrates agonist activity in forskolin-activated cAMP accumulation assays in CHO cells expressing human M2 and M4 receptors. The compound has been shown to reverse cognitive deficits induced by scopolamine in preclinical models. It produces both central and peripheral cholinergic effects.
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| ln Vivo |
In vivo, Milameline produces central cholinergic actions in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors. Oral administration is effective in reversing scopolamine-induced cognitive deficits in animal models. In early Alzheimer's disease patients, Milameline has a demonstrable effect on cerebral blood flow, with effects appearing most prominent in frontal and subcortical regions. It demonstrates promnestic effects in animal models and may impact regional cerebral blood flow.
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| Enzyme Assay |
Generic protocol for radioligand binding to human mAChR subtypes: CHO cells expressing human M1, M2, M3, or M4 receptors are harvested and membranes prepared. Membranes are incubated with [3H]QNB (1 nM) or [3H]CMD (1 nM) as radioligand and various concentrations of test compound (0.1 nM to 100 uM) in binding buffer (50 mM Tris-HCl, pH 7.4) for 60-90 minutes at room temperature. Bound radioactivity is separated by filtration through GF/B filters presoaked in 0.3% polyethyleneimine. Non-specific binding is determined with 1 uM atropine. IC50 values are calculated by non-linear regression. For Milameline, IC50 values for M1-M4 subtypes ranged from 1.1-1.9 uM.
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| Cell Assay |
A typical cell-based assay: CHO cells stably expressing human M2 or M4 muscarinic receptors are cultured in 96-well plates. Cells are labeled with [3H]adenine (1 uCi/well) for 2 hours at 37degC to measure cAMP accumulation. After washing, cells are incubated with varying concentrations of Milameline (1 nM to 100 uM) in the presence of 3-isobutyl-1-methylxanthine (IBMX) for 15-30 minutes at 37degC. The reaction is terminated, and [3H]cAMP is isolated by column chromatography. Forskolin (10 uM) is used to stimulate cAMP production. The percentage of cAMP accumulation relative to control is calculated, and EC50 values are determined.
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| Animal Protocol |
Generic in vivo protocol for cognitive assessment: Male Sprague-Dawley rats are administered scopolamine (1-3 mg/kg, i.p.) to induce cognitive deficits. Milameline hydroiodide (0.1-10 mg/kg) is administered orally 30-60 minutes prior to behavioral testing. Cognitive performance is assessed using the Morris water maze (escape latency, probe trial) or passive avoidance test (step-through latency). Central cholinergic effects are measured by monitoring cortical EEG or acetylcholine release via microdialysis. Peripheral cholinergic effects (salivation, lacrimation, tremor) are also recorded.
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| ADME/Pharmacokinetics |
Milameline is orally active and produces central cholinergic effects in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors. Powder should be stored at -20degC for up to 3 years, and in solvent at -80degC for up to 1 year. Specific half-life, Cmax, and AUC values are not publicly available in the literature. In early Alzheimer‘s disease studies, the drug showed effects on cerebral blood flow following oral administration.
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| Toxicity/Toxicokinetics |
Comprehensive published toxicology data are not available. In preclinical animal studies, Milameline produces both central and peripheral cholinergic effects (salivation, lacrimation, tremor) as expected for a muscarinic agonist. The compound has been evaluated in clinical trials in Alzheimer's disease patients, where cholinergic side effects are the primary safety concern. No specific LD50 values or repeat-dose toxicity data are publicly available. Standard laboratory safety precautions should be followed.
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| References | |
| Additional Infomation |
Milameline (CI-979/RU 35926) is a novel, orally active muscarinic agonist jointly developed by Parke-Davis and Roussel-UCLAF. It progressed into clinical development for Alzheimer's disease, with clinical studies including Phase 2 investigations and studies examining effects on cerebral blood flow in early AD patients (NCT numbers not available). However, Milameline does not appear to have received regulatory approval (FDA or EMA) and is not currently marketed for clinical use. Development may have been discontinued due to cholinergic side effects or lack of sufficient efficacy. The hydroiodide salt is used for research purposes only.
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| Appearance |
Yellow to orange solid powder
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| Synonyms |
CI 979 hydroiodide; RU 35926 hydroiodide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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