4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride (SSR125543A): A Potent and Selective Corticotrophin-Releasing Factor1Receptor Antagonist. I. Biochemical and Pharmacological Characterization

Gully, Danielle; Geslin, Michel; Serva, Laurence; Fontaine, Evelyne; Roger, P. M.; Lair, Christine; Darre, Valerie; Marcy, C. Howard; Rouby, Pierre-Eric; Simiand, Jacques; Guitard, Josette; Gout, G.; Steinberg, R.; Rodier, Daniel; Griebel, Guy; Soubrié, Philippe; Pascal, Marc; Pruss, Rebecca M.; Scatton, B.; Maffrand, Jean‐Pierre; Fur, G. Le

doi:10.1124/jpet.301.1.322

Cited by 73 publications

(36 citation statements)

References 38 publications

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“…17 Both SSR125543A and SSR149415 were found to inhibit ACTH secretion induced by acute restraint stress. 20,47 Moreover, elevated levels of adrenal steroids have been shown to profoundly reduce dentate cell proliferation. 14,15 Based on these findings, the action of SSR125543A and SSR149415 on hippocampal neurogenesis may be partly explained by a reduction of stress-induced hyperactivity of the HPA axis.…”

Section: Discussionmentioning

confidence: 99%

Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Griebel²,

et al. 2003

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Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF 1 and V 1b receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF 1 receptor antagonist SSR125543A, the V 1b receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF 1 and V 1b receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants. Keywords: depression; hippocampus; vasopressin; corticotrophin Despite extensive investigation, the mechanisms by which antidepressants exert their therapeutic effects are far from being fully understood. The dentate gyrus of the hippocampal formation is a brain region, which has focused much attention with respect to the effects of stress and the action of antidepressants. It is one of the few brain regions where adult neurogenesis has been documented in different species, including humans.1 Neurogenesis is defined by the proliferation of progenitor cells, giving rise to cells that migrate into the granule cell layers, and ultimately differentiate into neurons.2,3 Among the regulatory factors of neurogenesis, stressful events have been identified as potent inhibitors of dentate cell proliferation. [4][5][6][7][8] Chronic antidepressant treatment was reported to increase the rate of neurogenesis in adult brain. 9,10 Together, these findings led to the proposal that suppression of hippocampal neurogenesis in response to stress could be part of the structural remodelling occurring under pathological conditions and, accordingly, that restoration of this form of neural plasticity could be involved in the therapeutic effects of antidepressant treatment. [11][12][13] The precise mechanisms by which stress exerts these deleterious effects on hippocampal neurogenesis are unclear. However, this reduction appears to be mediated partly via st...

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Section: Discussionmentioning

confidence: 99%

Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Griebel²,

et al. 2003

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“…CP-154,526-01 (gift from Pfizer R&D), SSR125543Q (gift from Sanofi-Synthélabo R&D) and astressin 2-B (gift from Dr. Jean Rivier, Salk Institute, La Jolla, CA) were dissolved in DMSO made up in distilled water (pH 1.5) as a stock solution of 10 Ϫ2 M. CP-154,526 and SSR125543Q are specific inhibitors of CRF1 (14,20). Astressin2-B is a specific inhibitor of CRF2 (40).…”

Section: Methodsmentioning

confidence: 99%

Expression and effects of metabotropic CRF₁and CRF₂receptors in rat small intestine

Porcher¹,

Juhem²,

Peinnequin³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Porcher, Christophe, Aurélie Juhem, André Peinnequin, Valé-rie Sinniger, and Bruno Bonaz. Expression and effects of metabotropic CRF1 and CRF2 receptors in rat small intestine. Am J Physiol Gastrointest Liver Physiol 288: G1091-G1103, 2005. First published January 6, 2005; doi:10.1152/ajpgi.00302.2004.-Corticotropin-releasing factor (CRF)-like peptides mediate their effects via two receptor subtypes, CRF1 and CRF2; these receptors have functional implication in the motility of the stomach and colon in rats. We evaluated expression and functions of CRF1 and CRF2 receptors in the rat small intestine (i.e., duodenum and ileum). CRF1-2-like immunoreactivity (CRF1-2-LI) was localized in fibers and neurons of the myenteric and submucosal ganglia. CRF1-2-LI was found in nerve fibers of the longitudinal and circular muscle layers, in the mucosa, and in mucosal cells. Quantitative RT-PCR showed a stronger expression of CRF2 than CRF1 in the ileum, whereas CRF1 expression was higher than CRF2 expression in the duodenum. Functional studies showed that CRF-like peptides increased duodenal phasic contractions and reduced ileal contractions. CRF1 antagonists (CP-154,526 and SSR125543Q) blocked CRF-like peptide-induced activation of duodenal motility but did not block CRF-like peptide-induced inhibition of ileal motility. In contrast, a CRF2 inhibitor (astressin2-B) blocked the effects of CRF-like peptides on ileal muscle contractions but did not influence CRF-like peptide-induced activation of duodenal motility. These results demonstrate the presence of CRF1-2 in the intestine and demonstrate that, in vitro, CRF-like peptides stimulate the contractile activity of the duodenum through CRF1 receptor while inhibiting phasic contractions of the ileum through CRF2 receptor. These results strongly suggest that CRF-like peptides play a major role in the regulatory mechanisms that underlie the neural control of small intestinal motility through CRF receptors. astressin2-B; corticotropin-releasing factor receptors; urocortin CORTICOTROPIN-RELEASING FACTOR (CRF) is a 41-amino acid peptide recognized as a major regulator of pituitary adrenocorticotropin (54). This neuropeptide is the principal mediator of a wide variety of physiological responses caused by sustained stresses (2, 9, 22, 51). The paraventricular nucleus (PVN) of the hypothalamus is the main source for CRF in the brain (49). Recently, the addition of three mammalian neuropeptides, urocortin (Ucn) 1, Ucn 2, and Ucn 3, have expanded the family of CRF-related peptides (18).The CRF-like peptides mediate their effects via two receptor subtypes, CRF 1 and CRF 2␣ /CRF 2␤ , each encoded by distinct genes (6,8,27,41). Both receptors belong to the seventransmembrane domain family positively coupled to adenylate cyclase via G proteins (1,3,12). CRF 1 receptor mRNA is predominantly expressed in the brain under basal conditions (4, 45) but is increased in the PVN in acute stress (4), somatovisceral pain (50), and colitis (42). The distribution of the CRF 2 receptor variants differs by ...

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“…Schulz et al (1996) were the first to report a pyrazolopyrimidine CRF 1 antagonist, CP-154,526, with high affinity for the CRF 1 receptor and anxiolytic activity in rats. Additional CRF 1 antagonists, such as antalarmin, NBI 27914, DMP696, R121919, and SSR125543A, also exhibit CRF 1 antagonist properties in vitro and in vivo (He et al, 2000;McCarthy et al, 1999;Habib et al, 2000;Griebel et al, 2002;Gully et al, 2002;Heinrichs et al, 2002;Maciag et al, 2002;McElroy et al, 2002). Although a variety of the iodine-125-labeled peptides such as […”

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confidence: 99%

Pharmacological Characterization of a Novel Nonpeptide Antagonist Radioligand, (±)-N-[2-Methyl-4-methoxyphenyl]-1-(1-(methoxymethyl) propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine ([³H]SN003) for Corticotropin-Releasing Factor₁Receptors

Zhang¹,

Huang²,

Li³

et al. 2003

J Pharmacol Exp Ther

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The in vitro pharmacological profile of a novel small molecule corticotropin-releasing factor 1 (CRF 1 ) receptor antagonist, (Ϯ)- N-[2-methyl-4-methoxyphenyl]-1-(1-(methoxymethyl)propyl)-6-methyl-1H-1,2,3-triazolo [4,5-c] Corticotropin-releasing factor (CRF) was first isolated from ovine hypothalamus (Vale et al., 1981) and identified as a key secretagogue for ACTH release from the anterior pituitary.In the past 10 years, considerable progress has been made in understanding the physiological and potential pathological roles of the CRF system. In addition to its endocrine role in the regulation of the hypothalamic-pituitary-adrenal axis in response to stress, CRF appears to be implicated in a variety of other central and peripheral functions including arousal, anxiety-like behaviors, learning and memory, feeding, imArticle, publication date, and citation information can be found at

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4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride (SSR125543A): A Potent and Selective Corticotrophin-Releasing Factor₁Receptor Antagonist. I. Biochemical and Pharmacological Characterization

Abstract: 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-

Cited by 73 publications

References 38 publications

Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Expression and effects of metabotropic CRF₁and CRF₂receptors in rat small intestine

Pharmacological Characterization of a Novel Nonpeptide Antagonist Radioligand, (±)-N-[2-Methyl-4-methoxyphenyl]-1-(1-(methoxymethyl) propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine ([³H]SN003) for Corticotropin-Releasing Factor₁Receptors

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4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride (SSR125543A): A Potent and Selective Corticotrophin-Releasing Factor1Receptor Antagonist. I. Biochemical and Pharmacological Characterization

Abstract: 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-

Cited by 73 publications

References 38 publications

Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Expression and effects of metabotropic CRF1and CRF2receptors in rat small intestine

Pharmacological Characterization of a Novel Nonpeptide Antagonist Radioligand, (±)-N-[2-Methyl-4-methoxyphenyl]-1-(1-(methoxymethyl) propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine ([3H]SN003) for Corticotropin-Releasing Factor1Receptors

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Product

Resources

About

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride (SSR125543A): A Potent and Selective Corticotrophin-Releasing Factor₁Receptor Antagonist. I. Biochemical and Pharmacological Characterization

Expression and effects of metabotropic CRF₁and CRF₂receptors in rat small intestine

Pharmacological Characterization of a Novel Nonpeptide Antagonist Radioligand, (±)-N-[2-Methyl-4-methoxyphenyl]-1-(1-(methoxymethyl) propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine ([³H]SN003) for Corticotropin-Releasing Factor₁Receptors