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Purity: ≥98%
SB 258719 (SB-258719) is a novel, potent and selective 5-HT7 receptor antagonist with a pKi of 7.5. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism.
| Targets |
5-HT7 Receptor (pKi = 7.5)
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|---|---|
| ln Vitro |
Without significantly altering the peak response to 5-CT, SB 258719 (1, 3 and 10 μM; HEK 293 cells) causes a concentration-related rightward shift in the 5-CT concentration response curve [1].
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| ln Vivo |
The 5-CT-induced hypothermia is greatly attenuated by SB 258719 (5–20 mg/kg; i.p.) [2].
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| Enzyme Assay |
Measurement of [35S]-GTPgS binding [ 35S]-GTPgS binding to 5-HT7(a)/HEK293 membranes was measured using the method of Thomas et al. (1995a). Brie¯y, membranes (20 ± 30 mg protein) were preincubated (308C for 30 min) in 20 mM HEPES buer (pH 7.4) in the presence of 3 mM MgCl2, 100 mM NaCl, 10 mM GDP, 0.2 mM ascorbate and in the presence or absence of test drugs. Incubations (30 min, 308C) were started by addition of [ 35S]-GTPgS (0.1 ± 3 nM) followed by vigorous mixing and stopped by rapid ®ltration through Whatman GF/B ®lters followed by ®ve 1 ml washes with ice-cold buer containing 20 mM HEPES and 3 mM MgCl2. All determinations within an experiment were performed in duplicate. Radioactivity on the ®lters was determined using liquid scintillation spectrometry.[1]
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| Cell Assay |
HEK293 cells stably expressing the human 5-HT7(a) receptor were grown in Minimum Essential Medium (MEM) containing 10% dialysed foetal calf serum, G418 sulphate (1 mM), glutamine (2 mM) and non-essential amino acids (1%). Cells were grown to con¯uence, washed with phosphate buered saline (PBS), and pelleted by centrifugation (1000 g) in PBS containing EDTA (0.1 mM) and dithiothreitol (1 mM). Pellets were stored at 7808C prior to membrane preparation. For preparation of membranes, cell pellets were washed twice by homogenisation (Polytron, 15 s, setting 5) and centrifugation (50,000 g, 15 min, 48C) in 20 volumes of Tris HCl (25 mM pH 7.4) containing EDTA (0.1 mM). Membranes were then resuspended in buer and incubated (378C, 20 min). Following centrifugation and a further wash at 48C, the membranes were ®nally re-suspended at a membrane concentration equivalent to 2.56107 cells ml71 and stored at 7808C prior to use[1].
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| Animal Protocol |
Animal/Disease Models: Male Swiss Webster mouse (20-25 g) [2].
Doses: 5-20 mg/kg Route of Administration: intraperitoneal (ip) injection Experimental Results: Dramatically attenuated hypothermia induced by 5-CT. |
| References |
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| Additional Infomation |
1. The functional profile of the long form of the human cloned 5-HT7 receptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT7(a) receptor. 2. The receptor binding profile, determined by competition with [3H]-5-CT, was consistent with that previously reported for the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben zene sulfonamide) displayed high affinity (pKi 7.5) for the receptor. 3. In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT > 5-HT > 8-OH-DPAT) was the same in functional and binding studies. 4. Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA2 of 7.2+/-0.2 and slope not significantly different from 1, consistent with competitive antagonism. 5. The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism. 6. It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.[1]
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| Molecular Formula |
C18H30N2O2S
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|---|---|
| Molecular Weight |
338.5080037117
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| Exact Mass |
338.202799
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| CAS # |
195199-95-2
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| Related CAS # |
SB 258719 hydrochloride;1217674-10-6
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| PubChem CID |
5312148
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| Appearance |
Light yellow to yellow liquid
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| LogP |
4.946
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
23
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| Complexity |
452
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C1=CC=CC(C)=C1)(N(C)[C@H](C)CCN1CCC(C)CC1)(=O)=O
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| InChi Key |
UIZKHTBWJSUGOV-UNTBIKODSA-N
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| InChi Code |
InChI=1S/C18H30N2O2S.ClH/c1-15-8-11-20(12-9-15)13-10-17(3)19(4)23(21,22)18-7-5-6-16(2)14-18;/h5-7,14-15,17H,8-13H2,1-4H3;1H/t17-;/m1./s1
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| Chemical Name |
N,3-dimethyl-N-[(2R)-4-(4-methylpiperidin-1-yl)butan-2-yl]benzenesulfonamide Hydrochloride
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| Synonyms |
SB-258719 HCl; SB258719; SB258719; SB 258719; SB-258719; GF43CP5LXQ; SB258719; N,3-dimethyl-N-[(2R)-4-(4-methylpiperidin-1-yl)butan-2-yl]benzenesulfonamide; UNII-GF43CP5LXQ; CHEMBL12264; SB 258719 HCl.
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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 (~738.53 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6.25 mg/mL (18.46 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 62.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 6.25 mg/mL (18.46 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 62.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 6.25 mg/mL (18.46 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9541 mL | 14.7706 mL | 29.5412 mL | |
| 5 mM | 0.5908 mL | 2.9541 mL | 5.9082 mL | |
| 10 mM | 0.2954 mL | 1.4771 mL | 2.9541 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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