R121919 (NBI30775)
(Synonyms: 3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-A]嘧啶-7-胺,NBI30775) 目录号 : GC30792
R121919 (NBI30775) (NBI30775) 是一种有效的小分子 CRF1 受体拮抗剂，对 CRF1 受体的 Ki 为 2 至 5 nM，对 CRF2 受体、CRF 结合蛋白或 70 种其他受体类型的活性弱 1000 倍以上.
Cas No.:195055-03-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Rats: For the restraint stress,R121919 is dissolved in an aqueous 70% (v/v) polyethylene glycol 400 solution, and serially diluted in this vehicle to the appropriate concentrations. The drug is injected i.v. in a volume of 1 mL/kg to Male Sprague-Dawley rats. For the defensive withdrawal experiments, R121919 solutions are made fresh the night before each experiment. R121919 is dissolved in a vehicle consisting of 5% (v/v) polyethoxylated castor oil[1]. Mice: R121919 is dissolved in an aqueous. The drug is administered orally (1 mL/100 g bodyweight) via a feeding tube to six to ten mice per group; the doses applied are 0.5, 1.0 and 5.0 mg/kg for the DBA/2NCRL mice and 1.0, 5.0, and 30 mg/kg for the DBA/2Ola strain; an additional (vehicle) group of mice receives water, while a further group of mice (untreated controls) are spared the aforementioned manipulations[2]. |
References: [1]. Gutman DA, et al. The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress. J Pharmacol Exp Ther. 2003 Feb;304(2):874-80. | |
R121919 is a potent small-molecule CRF1 receptor antagonist with a Ki of 2 to 5 nM for the CRF1 receptor and over 1000-fold weaker activity at the CRF2 receptor, CRF-binding protein, or 70 other receptor types.
R121919 is a potent small-molecule CRF1 receptor antagonistwith high affinity for the CRF1 receptor (Ki=2-5 nM) and over 1000-fold weaker activity at the CRF2 receptor, CRF-binding protein, or 70 other receptor types[1].
R121919 reduces measures of both anxiety and depression in the depressed patients. R121919 dose dependently decreases adrenocorticopin hormone and corticosterone responses to restraint stress in rats. Peak plasma adrenocorticopin hormone and corticosterone concentrations at a dose of 10 mg/kg R121919 are 9 and 25%, respectively[1]. R121919 reduces levels of anxiety in mice with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets[2].
[1]. Gutman DA, et al. The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress. J Pharmacol Exp Ther. 2003 Feb;304(2):874-80. [2]. Post A, et al. Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919). Psychopharmacology (Berl). 2005 Jun;180(1):150-8.
| Cas No. | 195055-03-9 | SDF | |
| 别名 | 3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-A]嘧啶-7-胺,NBI30775 | ||
| Canonical SMILES | CCCN(C1=CC(C)=NC2=C(C3=CN=C(N(C)C)C=C3C)C(C)=NN21)CCC | ||
| 分子式 | C22H32N6 | 分子量 | 380.53 |
| 溶解度 | DMSO : 6.2 mg/mL (16.29 mM) | 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 | 2.6279 mL | 13.1396 mL | 26.2791 mL |
| 5 mM | 0.5256 mL | 2.6279 mL | 5.2558 mL |
| 10 mM | 0.2628 mL | 1.314 mL | 2.6279 mL |
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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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Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919)
Rationale: The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets. Objective: To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model. Results: Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775. Conclusion: NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.
Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism
Background: Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry "Translational Research in Addiction" symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF(1)) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking.
Methods: We review the biology of CRF(1) systems, the activity of CRF(1) receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF(1) receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF(1) receptor pharmacotherapy for alcohol dependence.
Results: The evidence suggests that brain penetrant-CRF(1) receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF(1) receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation.
Conclusions: Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF(1) receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence.
Involvement of CRFR1 in the Basolateral Amygdala in the Immediate Fear Extinction Deficit
Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR1 antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF6-33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR1 antagonist indicates their dependence on CRFR1 actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.
CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors
Stressful life events during childhood and adolescence are important risk factors for the development of psychopathologies later in life. The corticotropin releasing hormone (CRH) and the CRH receptor 1 (CRHR1) have been implicated in the link between early life adversity and adult anxiety and depression, with rodent studies identifying the very early postnatal period as highly susceptible to this programming. Here, we investigated whether stress exposure during the peripubertal period - comprising juvenility and puberty - is effective in inducing long-lasting changes in the expression of CRHR1 and CRHR2 in the hippocampus and amygdala, and whether treating animals with a CRHR1 antagonist following stress exposure could reverse behavioral alterations induced by peripuberty stress. We show that peripuberty stress leads to enhanced expression of the Crhr1, but not Crhr2, gene in the hippocampal CA1 and the central nucleus of the amygdala, in association with social deficits in the social exploration test and increased stress-coping behaviors in the forced swim test. Treatment with the CRHR1 antagonist NBI30775 (10 mg/kg) daily for 1 week (from P43 to P49), immediately following peripuberty stress exposure, prevented the occurrence of those psychopathological behaviors at adulthood. These findings highlight peripuberty as a period of plasticity for the enduring modulation of the CRHR1 system and support a growing body of data implicating the CRHR1 system in the programming effects of early life stress on eventual psychopathology. They also support recent evidence indicating that temporarily tackling CRHR1 during development might represent a therapeutic opportunity to correct behavioral trajectories linking early stress to adult psychopathology.
Corticotropin-releasing factor antagonists: recent advances and exciting prospects for the treatment of human diseases
Corticotropin-releasing factor (CRF) co-ordinates the neural, endocrine and immune responses of the body to stress. Several studies have implicated CRF in the etiology of anxiety, depression, substance abuse, stress-related gastrointestinal disorders and preterm labor, and intensive research into the design of safe and effective CRF antagonists is currently being pursued in several laboratories. Recently, improvements have been made not only in brain penetrance and in vivo activity in preclinical models for anxiety, depression and irritable bowel syndrome, but also in structural diversity for these compounds. Clinical data for R-121919 (NBI-30775; Neurocrine Biosciences Inc) raises the expectation that safe and potent CRF antagonists might be useful as drugs for the treatment of human diseases.