Osanetant
(Synonyms: 奥沙奈坦,SR142801) 目录号 : GC38829
An NK3 receptor antagonist
Cas No.:160492-56-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Osanetant is a neurokinin-3 (NK3) receptor antagonist (Ki = 0.21 nM in CHO cells expressing the human receptor).1 It is selective for NK3 over NK1 and NK2 receptors (Kis = >100 and 0.02 ?M, respectively).2 Osanetant inhibits contractions and acetylcholine release induced by neurokinin B in isolated guinea pig ileal strips in a concentration-dependent manner.1 It inhibits ovalbumin-induced increases in bronchoalveolar lavage fluid (BALF) neutrophil, eosinophil, and lymphocyte infiltration in an ovalbumin-sensitized mouse model of allergic asthma.3 Osanetant (5 and 10 mg/kg) increases the duration of social interaction, as well as reduces immobility time in the tonic immobility test, indicating anxiolytic-like and antidepressant-like activities, respectively, in gerbils.4
1.Emonds-Alt, X., Bichon, D., Ducoux, J.P., et al.SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptorLife Sci.56(1)PL27-PL32(1995) 2.Griebel, G., and Beeské, S.Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?Pharmacol. Ther.133(1)116-123(2012) 3.Nénan, S., Germain, N., Lagente, V., et al.Inhibition of inflammatory cell recruitment by the tachykinin NK3-receptor antagonist, SR 142801, in a murine model of asthmaEur. J. Pharmacol.421(3)201-205(2001) 4.Salomé, N., Stemmelin, J., Cohen, C., et al.Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbilsPharmacol. Biochem. Behav.83(4)533-539(2006)
| Cas No. | 160492-56-8 | SDF | |
| 别名 | 奥沙奈坦,SR142801 | ||
| Canonical SMILES | O=C(N1C[C@@](CCCN2CCC(N(C(C)=O)C)(C3=CC=CC=C3)CC2)(C4=CC=C(Cl)C(Cl)=C4)CCC1)C5=CC=CC=C5 | ||
| 分子式 | C35H41Cl2N3O2 | 分子量 | 606.62 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6485 mL | 8.2424 mL | 16.4848 mL |
| 5 mM | 0.3297 mL | 1.6485 mL | 3.297 mL |
| 10 mM | 0.1648 mL | 0.8242 mL | 1.6485 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Osanetant Sanofi-Synthélabo
Curr Opin Investig Drugs 2001 Jul;2(7):950-6.PMID:11757797doi
Osanetant is a neurokinin (NK3) receptor antagonist under development by Sanofi-Synthélabo (formerly Sanofi) as a potential treatment for schizophrenia [328910]. Sanofi was originally investigating its potential use as a treatment for psychosis and anxiety [169511]. Following phase IIa clinical trials [307656], [328910], [359231], Osanetant entered phase IIb development in February 2001 [409432]. Osanetant was the first potent and selective non-peptide antagonist described for the NK3 tachykinin receptor [176305]. It has a higher affinity for human and guinea pig NK3 receptors than for rat NK3 receptors [176305]. In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011 [346267].
Me-talnetant and Osanetant interact within overlapping but not identical binding pockets in the human tachykinin neurokinin 3 receptor transmembrane domains
Mol Pharmacol 2008 Jun;73(6):1736-50.PMID:18308898DOI:10.1124/mol.107.042754.
Recent clinical trials have indicated that neurokinin 3 receptor antagonists (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)-piperidin-3-yl]prop-1-yl}-4-phenylpiperidin-4-yl}-N-methylacetamine (SR142801; Osanetant) and (S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB223412; talnetant) may treat symptoms of schizophrenia. Using site-directed mutagenesis, rhodopsin-based modeling, [(3)H](S)-(-)-N-(alpha-ethylbenzyl)-3-methoxy-2-phenylquinoline-4-carboxamide (Me-talnetant) and [(3)H]Osanetant binding, and functional Schild analyses, we have demonstrated the important molecular determinants of neurokinin B (NKB), Me-talnetant, and Osanetant binding pockets. The residues Asn138(2.57), Asn142(2.61), Leu232(45.49), Tyr315(6.51), Phe342(7.39), and Met346(7.43) were found to be crucial for the NKB binding site. We observed that the M134(2.53)A, V169(3.36)M, F342(7.39)M, and S341(7.38)I/F342(7.39)M mutations resulted in the complete loss of [(3)H]Metalnetant and [(3)H]Osanetant binding affinities and also abolished their functional potencies in an NKB-evoked accumulation of [(3)H]inositol phosphates assay, whereas the mutations V95(1.42)A, N142(2.61)A, Y315(6.51)F, and M346(7.43)A behaved differently between the interacting modes of two antagonists. V95(1.42)A and M346(7.43)A significantly decreased the affinity and potency of Me-talnetant. Y315(6.51)F, although not affecting Me-talnetant, led to a significant decrease in affinity and potency of Osanetant. The mutation N142(2.61)A, which abolished the potency and affinity of Osanetant, led to a significant increase in the affinity and potency of Me-talnetant. The proposed docking mode was further validated using (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide (RO49085940), from another chemical class. It is noteworthy that the mutation F342(7.39)A caused an 80-fold gain of RO4908594 binding affinity, but the same mutation resulted in the complete loss of the affinity of Me-talnetant and partial loss of the affinity of Osanetant. These observations show that the binding pocket of Me-talnetant and Osanetant are overlapping, but not identical. Taken together, our data are consistent with the proposed docking modes where Me-talnetant reaches deeply into the pocket formed by transmembrane (TM)1, -2, and -7, whereas Osanetant fills the pocket TM3, -5, and -6 with its phenyl-piperidine moiety.
Neurokinin-3 receptor-specific antagonists talnetant and Osanetant show distinct mode of action in cellular Ca2+ mobilization but display similar binding kinetics and identical mechanism of binding in ligand cross-competition
Mol Pharmacol 2007 Mar;71(3):902-11.PMID:17172464DOI:10.1124/mol.106.029868.
Talnetant and Osanetant, two structurally diverse antagonists of neurokinin-3 receptor (NK3), displayed distinct modes of action in Ca2+ mobilization. Although talnetant showed a normal Schild plot with a slope close to unity and a Kb similar to its Ki value in binding, Osanetant presented an aberrant Schild with a steep slope (3.3 +/- 0.5) and a Kb value (12 nM) significantly elevated compared with its Ki value (0.8 nM) in binding. Kinetic binding experiments indicated a simple one-step binding mechanism with relatively fast on- and off-rates for both antagonists, arguing against slow onset of antagonism as the reason for abnormal Schild. This conclusion was supported by prolonged preincubation of antagonist that failed to improve the observed aberrant Schild. In ligand cross-competition binding, both talnetant and Osanetant displayed linear reciprocal plots of identical slope when [MePhe7]neurokinin B (NKB) was used as the other competition partner with 125I-[MePhe7]NKB as the radioligand, indicating competitive binding of either antagonist with regard to [MePhe7]NKB. Similar patterns were obtained when talnetant was tested against Osanetant, indicating competitive binding between the two antagonists as well. These results were reproduced when [3H]4-quinolinecarboxamide (SB222200), a close derivative of talnetant, was used as the radioligand. Taken together, these data strongly suggest binding of both talnetant and Osanetant at the orthosteric binding site with similar kinetic properties and do not support the hypothesis that the aberrant Schild observed in functional assays for Osanetant is derived from differences in the mechanism of binding for these NK3 antagonists.
Identification of a critical residue in the transmembrane domain 2 of tachykinin neurokinin 3 receptor affecting the dissociation kinetics and antagonism mode of Osanetant (SR 142801) and piperidine-based structures
J Med Chem 2009 Nov 26;52(22):7103-12.PMID:19817444DOI:10.1021/jm900948q.
In this study, we show that compound 3 (Osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr139(2.58) in human, corresponding to Ala114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).
A tachykinin NK3 receptor antagonist, SR 142801 (Osanetant), prevents substance P-induced bronchial hyperreactivity in guinea-pigs
Pulm Pharmacol Ther 1997 Oct-Dec;10(5-6):261-70.PMID:9778489DOI:10.1006/pupt.1998.0104.
Aerosolized substance P (0.1 M, for 30 min) induced airway hyperresponsiveness in guinea-pigs 24 h after they were pre-treated with salbutamol (8.7 mM by aerosol for 10 min) and phosphoramidon (0.1 mM by aerosol for 10 min). This was displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. The aim of this study was to investigate the effects of the non-peptide and potent tachykinin NK3 receptor antagonist, SR 142801 (Osanetant), in comparison with those of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (nolpitantium) and SR 48968 (saredutant) respectively, on substance P. When given once at 1 mg/kg i.p. 45 min before exposure to substance P, SR 142801 prevented both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. SR 142801 did not exhibit any tachykinin NK1 or NK2 antagonistic activity in experiments on guinea-pig isolated airways, in vitro or in vivo. The results suggest that tachykinin NK3 receptors might be involved in these substance P-induced effects on airways.