Vofopitant (GR 205171)
(Synonyms: GR 205171) 目录号 : GC33747
Vofopitant (GR 205171) 是有效的速激肽 NK1 受体拮抗剂，对人、大鼠和雪貂 NK1 受体的 pKis 分别为 10.6、9.5 和 9.8。
Cas No.:168266-90-8
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
Kinase experiment: | Tachykinin NK1 receptor binding assays are carried out in an assay volume of 200 μL, consisting of 50 μL of wash buffer (containing HEPES (50 mM) and MnC12 (3 mM), pH 7.4) or test compound (Vofopitant), 100 μL membrane suspension (3-5 μg of protein) in HEPES assay buffer (composition as above, but containing bacitracin, 80 μg/mL], leupeptin, 8 μg/mL], phosphoramidon, 2 μM and bovine serum albumin, 0.04%) and 50 μL of [3H]substance P (0.7-1.0 nM final concentration). The incubation is carried out at room temperature for 40 min. Non-specific binding is defined by the addition of CP-99,994 (1 μM)[1]. |
Animal experiment: | Effect of NK1 receptor antagonists administered i.p. on cortical [5-HT]ext of wild-type mice. Following collection of four baseline dialysate samples, freely moving wild-type mice are administered with either the vehicle or various NK1 receptor antagonists, Vofopitant (30 mg/kg; i.p.) or L733060 (40 mg/kg; i.p.). Dialysate samples are collected for a 0-120 min post-treatment period[3]. |
References: [1]. Gardner CJ, et al. GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity. Regul Pept. 1996 Aug 27;65(1):45-53. | |
Vofopitant is potent tachykinin NK1 receptor antagonist, with pKis of 10.6, 9.5, and 9.8 for human, rat and ferret NK1 receptor, respectively.
Vofopitant is potent tachykinin NK1 receptor antagonist, with pKis of 10.6, 9.5, and 9.8 for human, rat and ferret NK1 receptor, respectively. Vofopitant less potently inhibits rat 5-HT1A, bovine 5-HT1D, rat 5-HT2A, rat Histamine H1, guinea-pig Histamine H2 and rat Ca2+ channel, with pKis of 6.3, 6.6, 6.5, 6.5, 6.6, and 5.6, respectively. Vofopitant shows negligible affinity at NK2 and NK3, with pIC50 of <5.0[1]. GR205171 (300 µM) potentiates the effects of paroxetine on cortical [5-HT]ext, and inhibits paroxetine-induced increase in [5-HT]ext in the dorsal raphe nucleus[3].
Vofopitant (GR205171, 30 mg/kg, s.c.) increases the number of choices of the 25-s delayed reward in a T-maze[2]. Vofopitant (GR205171, 30 mg/kg, i.p.) increases the extracellular 5-HT levels in the frontal cortex of paroxetine-treated wild-type mice, rather than in wild-type mice and paroxetine-treated NK1 receptor knockout mice[3].
[1]. Gardner CJ, et al. GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity. Regul Pept. 1996 Aug 27;65(1):45-53. [2]. Loiseau F, et al. Antidepressant-like effects of agomelatine, melatonin and the NK1 receptor antagonist GR205171 in impulsive-related behaviour in rats. Psychopharmacology (Berl). 2005 Oct;182(1):24-32. Epub 2005 Sep 29. [3]. Guiard BP, et al. Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice. J Neurochem. 2004 Apr;89(1):54-63.
| Cas No. | 168266-90-8 | SDF | |
| 别名 | GR 205171 | ||
| Canonical SMILES | COC1=C(CN[C@@H]2[C@H](C3=CC=CC=C3)NCCC2)C=C(N4C(C(F)(F)F)=NN=N4)C=C1 | ||
| 分子式 | C21H23F3N6O | 分子量 | 432.44 |
| 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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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3125 mL | 11.5623 mL | 23.1246 mL |
| 5 mM | 0.4625 mL | 2.3125 mL | 4.6249 mL |
| 10 mM | 0.2312 mL | 1.1562 mL | 2.3125 mL |
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Safety of neurokinin-1 receptor antagonists
Expert Opin Drug Saf 2013 Sep;12(5):673-85.PMID:23706125DOI:10.1517/14740338.2013.804059.
Introduction: The substance P (SP)/neurokinin (NK)-1 receptor system is involved in many pathological processes. NK-1 receptor antagonists have many promising therapeutic indications. However, the only NK-1 receptor antagonist used in clinical practice is the drug aprepitant and its intravenously administered prodrug, fosaprepitant. In general, NK-1 receptor antagonists are safe and well tolerated. Areas covered: A search was carried out in Medline using the following terms: adverse events, aprepitant, casopitant, clinical trials, CP-122,721, ezlopitant, fosaprepitant, NK-1 receptor antagonists, randomized, safety, side effects, tolerability and Vofopitant. Expert opinion: Most clinical trials have focused on the antiemetic action of aprepitant in cancer patients treated with chemotherapy. However, the efficacy and safety of aprepitant have not been fully tested in other diseases in which the SP/NK-1 receptor system is involved (e.g., cancer, HIV, alcoholism); thus, clinical trials are required. The use of NK-1 receptor antagonists in oncology therapy is quite promising, but to date pharmacological therapy has not exploited the many possible therapies offered by such antagonists.
Effects of antidepressant drugs and GR 205171, an neurokinin-1 (NK1) receptor antagonist, on the response in the forced swim test and on monoamine extracellular levels in the frontal cortex of the mouse
Neurosci Lett 2003 Jul 17;345(2):73-6.PMID:12821174DOI:10.1016/s0304-3940(03)00305-7.
We tested fluoxetine, bupropion and GR 205171, a selective neurokinin-1 receptor antagonist on forced swimming test (FST) response and on levels of monoamines in frontal cortex of CD1 mice by microdialysis techniques. All drugs decreased immobility time. Fluoxetine augmented all monoamines, bupropion enhanced catecholamines, and GR 205171 was totally ineffective. Results suggest that FST response may not be related to levels of monoamines in the mouse frontal cortex.
Potential of substance P antagonists as antiemetics
Drugs 2000 Sep;60(3):533-46.PMID:11030465DOI:10.2165/00003495-200060030-00002.
The introduction of serotonin 5-HT3 receptor antagonists into clinical practice allowed for a dramatic improvement in the management of nausea and vomiting. Despite this, postoperative and chemotherapy-induced emesis remains a significant, unresolved issue in many patients even when a combination of antiemetic drugs is used. Numerous neurotransmitters have been implicated in triggering emesis; however, the tachykinin substance P, by virtue of its localisation within both the gastrointestinal vagal afferent nerve fibres and brainstem emetic circuitry, and its ability to induce vomiting when administered intravenously, is thought to play a key role in emetic responses. Because substance P is the most likely endogenous ligand for the neurokinin-1 (NK1) receptor, the development of nonpeptide NK1 receptor antagonists led scientists to evaluate these compounds as antiemetics. The five NK1 receptor inhibitors that have been studied initially in humans are: Vofopitant (GR-205171), CP-122721, ezlopitant (CJ-11974), MK-869 (L-754030) and its prodrug L-758298. Except for monotherapy in acute cisplatin-induced emesis, this new class of drugs has proven to be highly effective in the control of both chemotherapy-induced nausea and vomiting, and postoperative nausea and vomiting. No major adverse event was reported in the preliminary trials. Further investigation is mandatory in order to assess the optimal treatment regimen and to make sure the wide spectrum activity of the NK1 receptor inhibitors does not cause significant adverse effects in the context of the treatment of nausea and vomiting.
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2006 Oct;28(8):533-91.PMID:17136234doi
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; LA-419, lacosamide, landiolol, lanthanum carbonate, lidocaine/prilocaine, liposomal cisplatin, lutropin alfa; Matuzumab, MBP(82-98), mecasermin, MGCD-0103, MMR-V, morphine hydrochloride, mycophenolic acid sodium salt; Natalizumab, NCX-4016, neridronic acid, nesiritide, nilotinib, NSC-330507; O6-benzylguanine, olanzapine/fluoxetine hydrochloride, omalizumab; Panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pemetrexed disodium, perospirone hydrochloride, pexelizumab, phorbol 12-myristate 13-acetate, pneumococcal 7-valent conjugate vaccine, posaconazole, pramiconazole, prasugrel, pregabalin, prilocaine; rAAV-GAD65, raclopride, rasagiline mesilate, retapamulin, rosuvastatin calcium, rotigotine, rufinamide; SarCNU, SB-743921, SHL-749, sirolimus-eluting stent, sitaxsentan sodium, sorafenib; TachoSil, tadalafil, talampanel, Taxus, tegaserod maleate, telithromycin, telmisartan/hydrochlorothiazide, temsirolimus, tenatoprazole, teriflunomide, tetrathiomolybdate, ticilimumab, timcodar dimesilate, tipifarnib, tirapazamine, TPI, tramiprosate, trifluridine/TPI, trimethoprim; Ularitide, Urocortin 2; Valdecoxib, valganciclovir hydrochloride, valproate magnesium, valspodar, vardenafil hydrochloride hydrate, vitespen, Vofopitant hydrochloride, volociximab, vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, zotarolimus, zotarolimus-eluting stent.
Sustained pharmacological blockade of NK1 substance P receptors causes functional desensitization of dorsal raphe 5-HT 1A autoreceptors in mice
J Neurochem 2005 Dec;95(6):1713-23.PMID:16219031DOI:10.1111/j.1471-4159.2005.03488.x.
Antagonists at NK1 substance P receptors have demonstrated similar antidepressant properties in both animal paradigms and in human as selective serotonin reuptake inhibitors (SSRIs) that induce desensitization of 5-HT 1A autoreceptors within the dorsal raphe nucleus (DRN). We investigated whether this receptor adaptation also occurs upon NK1 receptor blockade. C57B/L6J mice were treated for 21 days with the selective NK1 receptor antagonist GR 205171 (10 mg/kg daily) through subcutaneously implanted osmotic mini pumps, and DRN 5-HT 1A autoreceptor functioning was assessed using various approaches. Recording of DRN serotonergic neurons in brainstem slices showed that GR 205171 treatment reduced (by approximately 1.5 fold) the potency of the 5-HT 1A receptor agonist, ipsapirone, to inhibit cell firing. In parallel, the 5-HT 1A autoreceptor-mediated [35S]GTP-gamma-S binding induced by 5-carboxamidotryptamine onto the DRN in brainstem sections was significantly decreased in GR 205171-treated mice. In vivo microdialysis showed that the cortical 5-HT overflow caused by acute injection of the SSRI paroxetine (1 mg/kg) was twice as high in GR 205171-treated as in vehicle-treated controls. In the DRN, basal 5-HT outflow was significantly enhanced by GR 205171 treatment. These data supported the hypothesis that chronic NK1 receptor blockade induces a functional desensitization of 5-HT 1A autoreceptors similar to that observed with SSRIs.