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| 5mg |
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| Targets |
Target: Human neurokinin‑3 (NK‑3) receptor – binding Ki = 13 nM (displacement of [¹²⁵I]MePhe⁷‑NKB from hNK‑3‑CHO cell membranes) [1].
Target: Human neurokinin‑2 (NK‑2) receptor – binding Ki = 1221 nM (displacement of [¹²⁵I]NKA from hNK‑2‑CHO membranes) [1]. Target: Human neurokinin‑1 (NK‑1) receptor – binding Ki > 100 μM (displacement of [³H]substance P from hNK‑1‑CHO membranes) [1]. |
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| ln Vitro |
The NK3 receptor agonist Senktide causes a contractile response that is antagonistic to SB 218795 (3–30 nM) in a concentration-dependent and surmountable way [2]. The rabbit iris sphincter's contractile response to the NK3 receptor agonist [MePhe7]-NKB is unaffected by SB 218795 (0.3-3 μM) [2].
In Vitro: In radioligand binding assays using membranes from CHO cells stably expressing human neurokinin receptors, SB-218795 showed high affinity for hNK‑3 (Ki = 13 ± 3 nM), moderate affinity for hNK‑2 (Ki = 1221 ± 189 nM) and very low affinity for hNK‑1 (Ki > 100 μM), indicating >90‑fold selectivity for hNK‑3 over hNK‑2 and >7000‑fold over hNK‑1 [1]. In the rabbit isolated iris sphincter muscle, SB-218795 (0.3 μM and 3 μM) surmountably antagonized contractile responses to the selective NK‑3 receptor agonist senktide, with mean apparent pKB = 7.4 ± 0.06 (n = 6). At 3 μM, it did not affect contractions induced by substance P or by transmural nerve stimulation (2 Hz), demonstrating selectivity for NK‑3 over NK‑1 receptors in this tissue. In contrast, SB-218795 (0.3 μM and 3 μM) had no inhibitory effect on contractions elicited by the NK‑3 receptor agonist [MePhe⁷]‑NKB, although it steepened the concentration‑effect curve (Hill coefficient increased from 0.54 to 1.56‑1.60) [2]. |
| ln Vivo |
SB 218795 (0.25-1 mg/kg; iv) suppresses rabbits' Senktide-induced miosis, with a maximal rate of 78% inhibition [2].
In Vivo: In conscious male New Zealand White rabbits, intravenous administration of senktide (25 μg) induced bilateral miosis (mean pupillary constriction 4.25±0.25 mm). Pretreatment with SB-218795 (0.5 and 1.0 mg/kg, i.v., given 2.5 min before senktide) significantly inhibited senktide‑induced pupillary constriction, with maximum inhibition of 78% (n = 3). A lower dose (0.25 mg/kg, i.v.) was inactive. The antagonist alone had no effect on baseline pupillary diameter [2]. In the same model, SB-218795 (1.5 mg/kg, i.v.) also antagonized senktide‑induced miosis, as did the reference NK‑3 antagonist SR 142801 [2]. |
| Cell Assay |
Cell Assay (radioligand binding): For hNK‑3 receptor competition binding, membranes from CHO cells stably expressing hNK‑3 (~15 μg protein) were incubated with 0.15 nM [¹²⁵I]MePhe⁷‑NKB in 50 mM Tris (pH 7.4), 4 mM MnCl₂, 1 μM phosphoramidon, 0.1% ovalbumin, with or without SB-218795 at various concentrations, for 90 min at 25 °C. Incubations were terminated by rapid filtration through Whatman GF/C filters presoaked in 0.5% BSA. Radioactivity was counted. Non‑specific binding was defined with 0.5 μM cold MePhe⁷‑NKB. Ki was calculated from IC₅₀ via Cheng‑Prusoff equation [1].
For hNK‑2 binding, similar conditions used 0.15 nM [¹²⁵I]NKA, filters presoaked in 0.1% PEI [1]. For hNK‑1 binding, membranes were incubated with 1.0 nM [³H]substance P in 25 mM Tris (pH 7.4), 2 mM CaCl₂, 2 mM MgCl₂, 1 μM phosphoramidon, 0.1% ovalbumin for 45 min at 25 °C; filters presoaked in BSA [1]. Functional assay in isolated rabbit iris sphincter muscle: Male New Zealand White rabbits (2‑3 kg) were euthanized by i.v. pentobarbitone. Iris sphincter strips were mounted in 50 mL organ baths containing Krebs‑Henseleit solution (37 °C, 95% O₂/5% CO₂) under 400 mg resting tension. After equilibration, a reference contraction to carbachol (10 μM) was obtained. Tissues were then incubated with atropine (1 μM) and the NK‑1 antagonist CP 99994 (1 μM) for the remainder of the experiment. SB-218795 (0.3 μM or 3 μM) or vehicle (DMSO) was added for 120 min, then cumulative concentration‑effect curves to senktide or [MePhe⁷]‑NKB were constructed. Responses were expressed as % of carbachol maximum. Apparent pKB was calculated from single concentration using Gaddum‑Schild equation: pKB = -log[B] + log(CR‑1) [2]. For neurogenic contraction, tissues were electrically stimulated (2 Hz, 0.3 ms, 20 V, 30 s) in the presence of atropine (1 μM) before and after 120 min incubation with 3 μM SB-218795 or 1 μM CP 99994 (positive control). Contractions were measured isometrically [2]. |
| Animal Protocol |
Animal protocol: Male New Zealand rabbits (2‑2.5 kg) were euthanized by a blow to the head. Segments of duodenum, jejunum, and ileum (10 mm long, whole thickness) were suspended in organ baths (10 mL capacity) containing Krebs solution (composition in mmol/L: NaCl 120, KCl 4.7, CaCl₂ 2.4, MgSO₄ 1.2, NaHCO₃ 24.5, KH₂PO₄ 1, glucose 5.6, pH 7.4, 37 °C) continuously gassed with 95% O₂/5% CO₂. Tissues were connected to isometric force transducers, passively stretched to 20 mN, and allowed to equilibrate for 60 min. Signals were amplified, recorded on a computer using MacLab System/8e, and digitized at 2 samples/s per channel. SB-218795 was added to the bath at 1 μmol/L, 15 min before agonist addition. Contractile responses were measured as integrated mechanical activity (mN/s) normalized per square millimeter of cross-sectional area and expressed as percentage of control agonist response. All experimental protocols were approved by the Ethical Committee of the University of Zaragoza (Spain) and complied with European Council legislation 86/609/EEC [3].
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| References |
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| Additional Infomation |
(2R)-2-[[oxo-(2-phenyl-4-quinolinyl)methyl]amino]-2-phenylacetic acid methyl ester is a member of the quinoline class of compounds.
Additional Info: SB-218795 is the (R)‑enantiomer of the methyl ester derivative; its (S)‑enantiomer (compound 66) has >70‑fold lower affinity (Ki = 926 nM). The compound was developed as a tool for studying NK‑3 receptor function. In the rabbit isolated iris sphincter, it shows competitive antagonism of senktide but no effect on [MePhe⁷]‑NKB‑induced contractions, supporting the existence of putative NK‑3 receptor subtypes. In vivo, it dose‑dependently blocks senktide‑induced miosis without behavioral side effects at the tested doses. The compound was synthesized via DCC/HOBT coupling of 2‑phenylquinoline‑4‑carboxylic acid with (R)‑methyl phenylglycinate [1][2]. |
| Exact Mass |
396.147
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|---|---|
| CAS # |
174635-53-1
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| PubChem CID |
6604858
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| Appearance |
White to off-white solid powder
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| Density |
1.237g/cm3
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| Boiling Point |
623.7ºC at 760 mmHg
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| Flash Point |
331ºC
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| Vapour Pressure |
1.78E-15mmHg at 25°C
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| Index of Refraction |
1.643
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| LogP |
4.936
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
583
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC([C@H](NC(C1=CC(C2C=CC=CC=2)=NC2=CC=CC=C12)=O)C1C=CC=CC=1)=O
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| InChi Key |
IUMQXQJZIHWLIN-HSZRJFAPSA-N
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| InChi Code |
InChI=1S/C25H20N2O3/c1-30-25(29)23(18-12-6-3-7-13-18)27-24(28)20-16-22(17-10-4-2-5-11-17)26-21-15-9-8-14-19(20)21/h2-16,23H,1H3,(H,27,28)/t23-/m1/s1
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| Chemical Name |
methyl (2R)-2-phenyl-2-[(2-phenylquinoline-4-carbonyl)amino]acetate
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| Synonyms |
SB-218795 SB 218795 SB218795
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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 : ~250 mg/mL (~630.61 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.) |
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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