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SB269970 (SB-269970A) is a novel and potent 5-HT7 receptor antagonist with pKi of 8.3, exhibits >50-fold selectivity against other receptors. SB269970 functions as a 5-HT7 receptor selective antagonist that exhibits at least a 100-fold selectivity against 5-HT7 across a range of receptors and enzymes. Moreover, SB269970 suppresses the 5-CT-stimulated adenylyl cyclase activity in both the guinea-pig hippocampal (pKB of 8.3) and 5-HT7(a)/HEK293 (pA2 of 8.5) membranes.
Physicochemical Properties
| Molecular Formula | C18H28N2O3S | |
| Molecular Weight | 352.49 | |
| Exact Mass | 352.18 | |
| Elemental Analysis | C, 61.33; H, 8.01; N, 7.95; O, 13.62; S, 9.10 | |
| CAS # | 201038-74-6 | |
| Related CAS # | SB-269970 hydrochloride; 261901-57-9 | |
| PubChem CID | 6604889 | |
| Appearance | Solid powder | |
| Boiling Point | 512.9ºC at 760 mmHg | |
| Flash Point | 264ºC | |
| Vapour Pressure | 3.87E-11mmHg at 25°C | |
| LogP | 4.425 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 24 | |
| Complexity | 497 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | OC1=CC=CC(S(=O)(N2[C@@H](CCN3CCC(C)CC3)CCC2)=O)=C1 |
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| InChi Key | HWKROQUZSKPIKQ-MRXNPFEDSA-N | |
| InChi Code | InChI=1S/C18H28N2O3S/c1-15-7-11-19(12-8-15)13-9-16-4-3-10-20(16)24(22,23)18-6-2-5-17(21)14-18/h2,5-6,14-16,21H,3-4,7-13H2,1H3/t16-/m1/s1 | |
| Chemical Name | 3-[(2R)-2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidin-1-yl]sulfonylphenol | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | 5-HT7 Receptor ( pKi = 8.3 ) | ||
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | SB269970 an antagonist of the 5-HT7 receptor with pKi of 8.3, exhibits >50-fold selectivity against other receptors. The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1))[1]. | ||
| Cell Assay |
1. The presence of 5-HT(7) receptor mRNA and protein in 5-HT neurons suggests that this receptor may act as a 5-HT autoreceptor. In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here.[2] The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1)). [1] |
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| Animal Protocol |
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| References |
[1]. Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist. Br J Pharmacol. 2000 Jun;130(3):539-48. [2]. The effect of SB-269970, a 5-HT(7) receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies. Br J Pharmacol. 2001 Apr;132(7):1574-80. [3]. Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats. PLoS One. 2013 Jun 11;8(6):e66695. [4]. The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat. Behav Brain Res. 2008 Aug 22;191(2):184-9. |
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| Additional Infomation |
3-[[(2R)-2-[2-(4-methyl-1-piperidinyl)ethyl]-1-pyrrolidinyl]sulfonyl]phenol is a sulfonamide. SB-269970 is an experimental drug developed by GlaxoSmithKline. In the studies performed with this agent, it has been suggested that SB-269970 acts either as a selective antagonist or inverse agonist of the serotonin receptor 7 (5-HT7). |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) | 30%propylene glycol+ 5%Tween 80+ 65%D5W: 30.0mg/ml (77.13mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8370 mL | 14.1848 mL | 28.3696 mL | |
| 5 mM | 0.5674 mL | 2.8370 mL | 5.6739 mL | |
| 10 mM | 0.2837 mL | 1.4185 mL | 2.8370 mL |