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| Targets |
μ Opioid Receptor/MOR
micro-opioid receptor (MOR). BMS-986121 is a selective positive allosteric modulator (PAM) of the micro opioid receptor. It binds to an allosteric site on MOR, distinct from the orthosteric agonist binding site, and enhances the efficacy and potency of orthosteric agonists (e.g., endomorphin-I, leu-enkephalin) without directly activating the receptor. |
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| ln Vitro |
The β-arrestin–recruitment response induced by a modest dose of endomorphin-I (PAM-detection mode) is greatly enhanced by BMS-986121 (1 μM~1 mM). When CHOμ cells are exposed to a concentration of endomorphin-I at ∼EC10 (30 pM), the forskolin-stimulated adenylyl cyclase activity is considerably inhibited, which is enhanced by BMS-986121. In CHO-μ cells, BMS-986121 (100 μM) causes leftward alterations in the potency of leu-enkephalin (sixfold) and endomorphin-I (fourfold) in the suppression of forskolin-stimulated cAMP-accumulation assays[1].
BMS-986121 (1 uM to 1 mM) significantly augments the beta-arrestin recruitment response produced by a low concentration of endomorphin-I (PAM detection mode). In CHOmicro cells, BMS-986121 (100 uM) produces leftward shifts in the potency of endomorphin-I (4-fold) and leu-enkephalin (6-fold) in inhibition of forskolin-stimulated cAMP accumulation assays. BMS-986121 (1 uM to 1 mM) significantly increases the inhibition of forskolin-stimulated adenylyl cyclase activity produced by an EC10 (30 pM) concentration of endomorphin-I in CHOmicro cells. These data indicate that BMS-986121 is an allosteric enhancer of MOR-mediated G-protein signaling and beta-arrestin recruitment. |
| ln Vivo |
No in vivo efficacy data are reported for BMS-986121. Based on its activity as a MOR PAM, it is expected to enhance opioid-mediated analgesia in vivo while potentially reducing side effects associated with direct MOR agonists (tolerance, dependence, respiratory depression). However, such in vivo studies have not been published for this compound. BMS-986121 may be used to study the therapeutic potential of allosteric modulation of MOR in pain and addiction.
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| Enzyme Assay |
Cell-free radioligand binding assays are not appropriate for PAMs. For allosteric interaction studies, membranes from CHO cells expressing human MOR are incubated with a fixed concentration of an orthosteric agonist radioligand (e.g., [3H]-DAMGO) in the presence of varying concentrations of BMS-986121 (0.01-1000 uM). Changes in radioligand binding kinetics (association/dissociation rates) are measured. Enhancement of orthosteric agonist binding affinity is determined by Scatchard analysis. BMS-986121 likely increases the affinity of orthosteric agonists without displacing the radioligand at the allosteric site.
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| Cell Assay |
Functional assays in CHOmicro cells (CHO cells stably expressing human micro-opioid receptor): For beta-arrestin recruitment, cells expressing a beta-arrestin2 luciferase reporter are treated with a low concentration of endomorphin-I (EC20-EC30) in the presence of BMS-986121 (1 uM to 1 mM). beta-Arrestin recruitment is measured by luminescence. For cAMP accumulation inhibition, CHOmicro cells are pre-incubated with BMS-986121 (1-1000 uM) for 15-30 min and then stimulated with a low concentration of endomorphin-I (30 pM) in the presence of forskolin (10 uM). Intracellular cAMP levels are measured by HTRF cAMP kit. BMS-986121 enhances the inhibitory effect of endomorphin-I on cAMP accumulation, as evidenced by leftward shifts in endomorphin-I and leu-enkephalin concentration-response curves. Colony formation or cell viability assays may be performed to assess compound cytotoxicity.
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| Animal Protocol |
No published in vivo animal protocols are available for BMS-986121. For potential in vivo PAM studies, BMS-986121 would be administered to rodents (i.p. or p.o.) alone or in combination with a low dose of a micro opioid agonist (e.g., morphine, endomorphin-I). Tail-flick or hot-plate tests would be used to assess analgesia. The ability of BMS-986121 to enhance agonist potency with reduced tolerance or respiratory depression would be evaluated. No such studies have been published. BMS-986121 is primarily an in vitro research tool at present.
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| ADME/Pharmacokinetics |
No specific pharmacokinetic data are reported for BMS-986121. The molecular weight is 366.22 (C15H9Cl2N3O2S). CAS# 313671-26-0. Purity ≥98%. Storage: -20degC. DMSO solubility is >10 mg/mL. As a small molecule (MW ~366), BMS-986121 is expected to have moderate oral bioavailability and to cross the BBB, but this has not been confirmed experimentally. PK parameters (t1/2, Cmax, AUC, F%) are not reported. The compound is for in vitro research use only, pending in vivo validation.
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| Toxicity/Toxicokinetics |
No specific toxicity data are reported for BMS-986121. In published cell-based assays (CHOmicro cells), no overt cytotoxicity was reported at concentrations up to 1 mM. However, comprehensive toxicological assessments (hERG, Ames, acute toxicity in rodents) have not been performed. BMS-986121 has not entered clinical trials and is not FDA-approved. Because it is an allosteric modulator that does not directly activate MOR, it is expected to have a more favorable safety profile than direct agonists, but this is speculative.
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| References |
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| Additional Infomation |
Other information: BMS-986121 is a research compound, not FDA-approved. CAS# 313671-26-0. It is a positive allosteric modulator of the micro-opioid receptor extracted from patent WO2014107344. It represents a new chemical scaffold for micro receptor PAMs and is a valuable tool for studying the therapeutic potential of allosteric modulation of opioid receptors in pain management and addiction. For research use only.
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| Molecular Formula |
C15H9CL2N3O2S
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|---|---|
| Molecular Weight |
366.22
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| Exact Mass |
364.979
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| CAS # |
313671-26-0
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| PubChem CID |
2323217
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
5.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
23
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| Complexity |
408
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C=C(C2=CC=C([N+]([O-])=O)C=C2)N=C1NC1=C(Cl)C=CC=C1Cl
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| InChi Key |
AOCLKIVPDLQCOF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H9Cl2N3O2S/c16-11-2-1-3-12(17)14(11)19-15-18-13(8-23-15)9-4-6-10(7-5-9)20(21)22/h1-8H,(H,18,19)
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| Chemical Name |
N-(2,6-dichlorophenyl)-4-(4-nitrophenyl)-1,3-thiazol-2-amine
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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: 100 mg/mL (273.06 mM)
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7306 mL | 13.6530 mL | 27.3060 mL | |
| 5 mM | 0.5461 mL | 2.7306 mL | 5.4612 mL | |
| 10 mM | 0.2731 mL | 1.3653 mL | 2.7306 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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