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| ln Vitro |
137 exhibited high binding affinity for the sigma-1 receptor (Ki σ₁ = 1.06 nM) and excellent selectivity over the sigma-2 receptor (Ki σ₂ = 1425 nM, selectivity σ₂/σ₁ = 1344-fold). [1]
In a functional phenytoin-shift assay, 137 showed a Ki ratio (without/with phenytoin) of 0.87, confirming its antagonist profile at the sigma-1 receptor. [1] 137 showed weak affinity for the hERG potassium channel (IC₅₀ = 6.98 µM), indicating a low potential for cardiac toxicity. [1] In a broad selectivity panel against receptors and ion channels implicated in pain (e.g., μ-opioid, serotonin, NMDA, Nav1.7, TRPV1), 137 showed no significant affinity (% inhibition < 50% at 1 µM). [1] |
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| ln Vivo |
In the mouse formalin test, pretreatment with 137 (80 mg/kg, ip) significantly reduced pain responses in both Phase I (licking time: 12.65 ± 5.07 s) and Phase II (licking time: 37.41 ± 8.89 s), with effects comparable to the reference sigma-1 antagonist S1RA. The antinociceptive effect was dose-dependent (ED₅₀ values: 48.36 ± 5.11 mg/kg for Phase I and 42.15 ± 3.96 mg/kg for Phase II). [1]
In the rat chronic constriction injury (CCI) model of neuropathic pain, single and repeated oral administration of 137 (20, 40, 80 mg/kg) dose-dependently inhibited both mechanical allodynia (von Frey test) and thermal hyperalgesia (plantar test). The ED₅₀ values for single-dose treatment were 58.25 ± 6.04 mg/kg (mechanical) and 47.23 ± 3.87 mg/kg (thermal). [1] In the rotarod test, 137 at analgesic doses did not impair motor coordination in mice, unlike the positive control pregabalin. [1] |
| Enzyme Assay |
The sigma-1 receptor binding affinity of 137 was determined using guinea pig brain membranes. Membranes were incubated with the radioligand [³H]-(+)-pentazocine and various concentrations of the test compound (10⁻⁵ to 10⁻¹⁰ M) in Tris-HCl buffer (pH 8.0) at 25°C for 180 minutes. Nonspecific binding was defined using haloperidol (10 µM). The incubation was terminated by rapid vacuum filtration through GF/B filters, followed by washing and scintillation counting. Ki values were calculated using the Cheng-Prusoff equation. [1]
The sigma-2 receptor binding assay was conducted similarly using guinea pig brain membranes incubated with [³H]-DTG in the presence of (+)-SKF-10047 (400 nM) to block sigma-1 sites. Incubation proceeded at 25°C for 120 minutes. Nonspecific binding was defined with DTG (10 µM). [1] |
| Cell Assay |
The potential of 137 to block the hERG potassium channel was assessed using the whole-cell patch-clamp technique on HEK293 cells stably expressing hERG channels. Cells were voltage-clamped, and tail currents were measured at -50 mV following a depolarizing pulse to +50 mV. The effect of 137 was tested at concentrations of 0.3, 1, 3, and 10 µM. The IC₅₀ value was determined from the concentration-response curve of the tail current inhibition. [1]
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| Animal Protocol |
Formalin Test: Mice were administered 137 (dissolved in 30% PEG 400) or vehicle intraperitoneally (ip) 15 minutes before an intraplantar injection of 2.5% formalin solution (20 µL) into the hind paw. The time spent licking or biting the injected paw was recorded during Phase I (0-5 min) and Phase II (15-45 min) post-injection. [1]
Chronic Constriction Injury (CCI) Model: Under anesthesia, the right sciatic nerve of rats was exposed and loosely ligated with four silk sutures. Sham-operated rats underwent exposure without ligation. Starting on day 14 post-surgery, rats were orally administered 137 (suspended in 0.5% methylcellulose) or vehicle twice daily for 4 consecutive days. Mechanical allodynia was assessed using von Frey filaments (up-down method), and thermal hyperalgesia was assessed using a plantar test apparatus (radiant heat) on day 15 (single dose) and day 18 (repeated dose). [1] Rotarod Test: Mice were trained to stay on a rotating rod (10 rpm). After ip administration of 137 or vehicle, the latency to fall from the rod was recorded at 30, 60, 90, and 120 minutes. [1] Acute Toxicity Study: Mice were orally administered a single dose of 137 (suspended in 0.5% methylcellulose) at doses of 200, 500, 1000, 1500, and 2000 mg/kg. Mortality was recorded over 24 hours, and the LD₅₀ was calculated. [1] |
| ADME/Pharmacokinetics |
In rats, after a single intravenous (iv) injection of 16 mg/kg, the half-life (t₁/₂) of compound 137 was 10.57 hours, and the AUC₀－∞ was 3686.17 ng·h/mL. [1] After a single oral (po) administration of 320 mg/kg, the half-life (t₁/₂) of compound 137 was 3.81 hours, the time to peak concentration (Tmax) was 0.5 hours, the peak concentration (Cmax) was 17394.90 ng/mL, and the AUC₀－∞ was 55393.45 ng·h/mL. [1] The oral bioavailability (F) of compound 137 in rats was calculated to be 75.1%. [1]
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| Toxicity/Toxicokinetics |
Following oral administration to mice, the median lethal dose (LD₅₀) of 137 was greater than 2000 mg/kg. [1] No treatment-related adverse reactions or motor disorders were observed in behavioral tests at effective doses. [1]
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| References | |
| Additional Infomation |
137 (5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine) is a novel, highly effective, and selective σ-1 receptor antagonist derived from pyrimidine compounds. [1] Based on its efficacy in preclinical pain models, favorable pharmacokinetic characteristics, and safety profile, this compound is considered a potential drug for treating neuropathic pain. [1]
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| Molecular Formula |
C19H23CLFN3O
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|---|---|
| Molecular Weight |
363.856827020645
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| Exact Mass |
363.151
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| CAS # |
1639220-17-9
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| PubChem CID |
118723363
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| Appearance |
White to off-white solid powder
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| LogP |
4.5
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
25
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| Complexity |
389
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C(C)N=C(C2C=CC(=CC=2)F)N=C1OCCCN1CCCCC1
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| InChi Key |
OAIHSWLLDNASTO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H23ClFN3O/c1-14-17(20)19(25-13-5-12-24-10-3-2-4-11-24)23-18(22-14)15-6-8-16(21)9-7-15/h6-9H,2-5,10-13H2,1H3
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| Chemical Name |
5-chloro-2-(4-fluorophenyl)-4-methyl-6-(3-piperidin-1-ylpropoxy)pyrimidine
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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 |
| 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) |
DMSO : ~12.5 mg/mL (~34.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7483 mL | 13.7415 mL | 27.4831 mL | |
| 5 mM | 0.5497 mL | 2.7483 mL | 5.4966 mL | |
| 10 mM | 0.2748 mL | 1.3742 mL | 2.7483 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
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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