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Guy Griebel - One of the best experts on this subject based on the ideXlab platform.
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an overview of ssr149415 a selective nonpeptide Vasopressin V1b Receptor antagonist for the treatment of stress related disorders
Cns Drug Reviews, 2006Co-Authors: Claudine Serradeille Gal, Jean Wagnon, Guy Griebel, Bernard Tonnerre, Richard Roux, Georges Garcia, Alain AulombardAbstract:Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central Vasopressin V1b Receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active Vasopressin V1b Receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V1b Receptors and displays a highly selective profile with regard to a large number of Receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V1b Receptor activation by AVP, such as intracellular Ca2+ increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.
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An Overview of SSR149415, a Selective Nonpeptide Vasopressin V1b Receptor Antagonist for the Treatment of Stress‐Related Disorders
CNS drug reviews, 2006Co-Authors: Claudine Serradeille Gal, Jean Wagnon, Guy Griebel, Bernard Tonnerre, Richard Roux, Georges Garcia, Aulombard AlainAbstract:Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central Vasopressin V1b Receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active Vasopressin V1b Receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V1b Receptors and displays a highly selective profile with regard to a large number of Receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V1b Receptor activation by AVP, such as intracellular Ca2+ increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.
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Differential roles of amygdaloid nuclei in the anxiolytic- and antidepressant-like effects of the V1b Receptor antagonist, SSR149415, in rats
Psychopharmacology, 2006Co-Authors: N. Salomé, Jeanne Stemmelin, Caroline Cohen, Guy GriebelAbstract:Rationale SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide), the first selective nonpeptide Vasopressin V1b Receptor antagonist has been shown to induce antidepressant—and anxiolytic-like effects following systemic administration, whereas intraseptal infusion of the drug engender antidepressant—but not anxiolytic-like effects.
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antidepressant like effects of the Vasopressin V1b Receptor antagonist ssr149415 in the flinders sensitive line rat
Pharmacology Biochemistry and Behavior, 2005Co-Authors: David H Overstreet, Guy GriebelAbstract:Abstract There is an increased interest in the potential of Vasopressin Receptor antagonists as antidepressants because of the involvement of Vasopressin in stress-related behavioral changes. The present study sought to provide confirmatory evidence for the antidepressant-like effects of the selective Vasopressin V1b Receptor antagonist SSR149415, which had been previously demonstrated in a variety of animal models. The Flinders Sensitive Line (FSL) rat, a selectively bred animal model of depression, was chronically treated for 14 days with SSR149415 (1, 10, and 30 mg/kg), vehicle, or desipramine (5 mg/kg) as a positive control. Approximately 22–24 h after the last treatment, the rats were exposed to a single 5-min session in a cylinder containing 25 °C water and immobility was recorded. A control group of Flinders Resistant Line (FRL) rats was included as a reference group as well as one treated with 10 mg/kg SSR149415. Vehicle-treated FSL rats exhibited much more immobility than the FRL rats, and desipramine-treated FSL rats had much lower scores, as expected. Treatment with SSR149415 reduced immobility in the FSL rats at all doses, but only the higher doses reduced it such that they were no longer different from the FRL rats. In contrast, SSR149415 did not alter the lower immobility of the FRL rats. The social interaction test of anxiety was also examined in the FSL rats, at 20–22 h after the last of the 14 injections. Results showed that the 10 and 30 mg/kg doses of SSR149415 increased the time spent in social interaction in the FSL rats, suggesting anxiolytic effects. These findings confirm the antidepressant-like potential of SSR149415 and suggest that it may also have anxiolytic effects. It is likely that the strategy of testing selective Vasopressin V1b Receptor antagonists will be fruitful.
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Non-peptide Vasopressin V1b Receptor antagonists as potential drugs for the treatment of stress-related disorders.
Current pharmaceutical design, 2005Co-Authors: Guy Griebel, Claudine Serradeille Gal, Jeanne Stemmelin, Philippe SoubrieAbstract:Since Vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active nonpeptide V1b Receptor antagonist, SSR149415, opened a new era for examining the role of Vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V1b Receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V1b Receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.
Akito Tanoue - One of the best experts on this subject based on the ideXlab platform.
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Enhanced glucose tolerance in the Brattleboro rat
Biochemical and biophysical research communications, 2011Co-Authors: Kazuaki Nakamura, Toshinori Aoyagi, Tatsuya Yamashita, Hiroyuki Fujiki, Junji Yamauchi, Toyoki Mori, Akito TanoueAbstract:Abstract [Arg8]-Vasopressin (AVP) plays a crucial role in regulating body fluid retention, which is mediated through the Vasopressin V2 Receptor in the kidney. In addition, AVP is involved in the regulation of glucose homeostasis via Vasopressin V1A and Vasopressin V1b Receptors. Our previous studies demonstrated that Vasopressin V1A Receptor-deficient (V1AR−/−) and V1b Receptor-deficient (V1bR−/−) mice exhibited hyperglycemia and hypoglycemia with hypoinsulinemia, respectively. These findings indicate that Vasopressin V1A Receptor deficiency results in decreased insulin sensitivity whereas Vasopressin V1b Receptor deficiency results in increased insulin sensitivity. In addition, Vasopressin V1A and Vasopressin V1b Receptor double-deficient (V1ABR−/−) mice exhibited impaired glucose tolerance, suggesting that the effects of Vasopressin V1b Receptor deficiency do not influence the development of hyperglycemia promoted by Vasopressin V1A Receptor deficiency, and that the blockage of both Receptors could lead to impaired glucose tolerance. However, the contributions of the entire AVP/Vasopressin Receptors system to the regulation of blood glucose have not yet been clarified. In this study, to further understand the role of AVP/Vasopressin Receptors signaling in blood glucose regulation, we assessed the glucose tolerance of AVP-deficient homozygous Brattleboro (di/di) rats using an oral glucose tolerance test (GTT). Plasma glucose and insulin levels were consistently lower in homozygous di/di rats than in heterozygous di/+ rats during the GTT, suggesting that the blockage of all AVP/Vasopressin Receptors resulting from the AVP deficiency could lead to enhanced glucose tolerance.
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Involvement of Vasopressin V1b Receptor in anti-anxiety action of SSRI and SNRI in mice.
Neuroscience research, 2009Co-Authors: Yuta Ishizuka, Akito Tanoue, Hiroshi Abe, Hiroshi Kannan, Yasushi IshidaAbstract:Arginine Vasopressin (AVP) is critical in the regulation of hypothalamic-pituitary-adrenal axis activity, a major component of the stress response. The Vasopressin V1b Receptor (V1bR) mediates the stimulatory effect of AVP on adrenocorticotropin release. Previous studies showed that AVP facilitates aggression while serotonin inhibits aggression by blocking the activity of the Vasopressin system. To examine whether the interaction of the V1bR and serotonin in the central nervous system controls anxiety-related behavior, we investigated the effects of acute and chronic treatment with a selective serotonin reuptake inhibitor (SSRI) and with a serotonin noradrenalin reuptake inhibitor (SNRI) on V1bR knockout (KO) mice and on V1bR antagonist (SSR149415)-treated mice. The effects were evaluated in experiments using an elevated plus-maze (EPM) test and a hole-board (HB) test, well established tests for evaluating anxiety-like behavior. For both the V1bR KO mice and V1bR antagonist-treated mice, acute treatment with either SSRI or SNRI did not change the time spent on the EPM open arms or the number of head dips in the HB. Chronic treatment of V1bR KO mice with SSRI did not change the amount of time spent on the open arms, the number of head dips, or the number of rearings, while chronic treatment with SNRI significantly increased the time spent on the open arms and the number of head dips. These results suggest that the anti-anxiety action of 5-HT reuptake inhibitors might partly involve V1bR regulating the anxiety behaviors.
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Both V(1A) and V(1B) Vasopressin Receptors deficiency result in impaired glucose tolerance.
European Journal of Pharmacology, 2009Co-Authors: Kazuaki Nakamura, Masami Hiroyama, Toshinori Aoyagi, Atsushi Sanbe, Junji Yamauchi, Shinji Kusakawa, Reiko Mizutani, Masazumi Kamohara, Kazuhiro Momose, Akito TanoueAbstract:[Arg8]-Vasopressin (AVP) is involved in the regulation of glucose homeostasis via Vasopressin V1A and Vasopressin V1b Receptor. Our previous studies have demonstrated that Vasopressin V1A Receptor deficient (V1AR−/−) mice exhibited hyperglycemia, Vasopressin V1b Receptor deficient (V1bR−/−) mice, in contrast, exhibited hypoglycemia with hypoinsulinemia. These findings indicate that Vasopressin V1A Receptor deficiency results in decreased insulin sensitivity, whereas Vasopressin V1b Receptor deficiency results in increased insulin sensitivity. In our previous and present studies, we used the glucose tolerance test to investigate glucose tolerance in mutant mice, lacking either the VasopressinV1A Receptor, the Vasopressin V1b Receptor, or both Receptors, that were kept on a high-fat diet. Glucose and insulin levels were lower in V1bR−/− mice than in wild type (WT) mice when both groups were fed the high-fat diet, which indicates that the insulin sensitivity of the V1bR−/− mice was enhanced. V1AR−/− mice on the high-fat diet, on the other hand, exhibited overt obesity, along with an impaired glucose tolerance, while WT mice on the high-fat diet did not. Next, in order to assess the effect of Vasopressin V1b Receptor deficiency on the development of glucose intolerance caused by Vasopressin V1A Receptor deficiency, we generated mice that were deficient for both Vasopressin V1A Receptor and Vasopressin V1b Receptor (V1ABR−/−), fed them a high-fat diet, and examined their glucose tolerances using the glucose tolerance test. Glucose tolerance was impaired in V1ABR−/− mice, suggesting that the effects of Vasopressin V1b Receptor deficiency could not influence the development of hyperglycemia promoted by Vasopressin V1A Receptor deficiency, and that blockade of both Receptors could lead to impaired glucose tolerance.
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Altered lipid metabolism in Vasopressin V1b Receptor-deficient mice.
European Journal of Pharmacology, 2008Co-Authors: Masami Hiroyama, Toshinori Aoyagi, Atsushi Sanbe, Kazuaki Nakamura, Reiko Mizutani, Yoko Fujiwara, Ryuji Tasaki, Akito TanoueAbstract:Abstract We previously reported that insulin sensitivity was increased in Vasopressin V1b Receptor-deficient (V1bR−/−) mice. Here, we investigate the lipid metabolism in V1bR−/− mice. Despite having lower body weight, V1bR−/− mice had significantly greater fat weight of the epididymal white adipose tissue than V1bR+/+ mice. Glycerol production and β-oxidation were suppressed in V1bR−/− mice under a fasting condition, and isoproterenol-stimulated lipolysis in differentiated adipocytes was significantly decreased in V1bR−/− mice. These results indicated that lipolysis was inhibited in V1bR−/− mice. On the other hand, lipogenesis was promoted by the increased metabolism from glucose to lipid. Furthermore, our in vivo and in vitro analyses showed that the secretion of adiponectin was increased in V1bR−/− mice, while the serum leptin level was lower in V1bR−/− mice. These findings indicated that the insulin sensitivity and lipid metabolism were altered in V1bR−/− mice and that the increased insulin sensitivity could contribute to the suppressed lipolysis and enhanced lipogenesis, which consequently resulted in the increased fat weight in V1bR−/− mice.
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Altered lipid metabolism in Vasopressin V1b Receptor-deficient mice.
European journal of pharmacology, 2008Co-Authors: Masami Hiroyama, Toshinori Aoyagi, Atsushi Sanbe, Kazuaki Nakamura, Reiko Mizutani, Yoko Fujiwara, Ryuji Tasaki, Akito TanoueAbstract:We previously reported that insulin sensitivity was increased in Vasopressin V(1B) Receptor-deficient (V(1B)R(-/-)) mice. Here, we investigate the lipid metabolism in V(1B)R(-/-) mice. Despite having lower body weight, V(1B)R(-/-) mice had significantly greater fat weight of the epididymal white adipose tissue than V(1B)R(+/+) mice. Glycerol production and beta-oxidation were suppressed in V(1B)R(-/-) mice under a fasting condition, and isoproterenol-stimulated lipolysis in differentiated adipocytes was significantly decreased in V(1B)R(-/-) mice. These results indicated that lipolysis was inhibited in V(1B)R(-/-) mice. On the other hand, lipogenesis was promoted by the increased metabolism from glucose to lipid. Furthermore, our in vivo and in vitro analyses showed that the secretion of adiponectin was increased in V(1B)R(-/-) mice, while the serum leptin level was lower in V(1B)R(-/-) mice. These findings indicated that the insulin sensitivity and lipid metabolism were altered in V(1B)R(-/-) mice and that the increased insulin sensitivity could contribute to the suppressed lipolysis and enhanced lipogenesis, which consequently resulted in the increased fat weight in V(1B)R(-/-) mice.
Claudine Serradeille Gal - One of the best experts on this subject based on the ideXlab platform.
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Biological characterization of rodent and human Vasopressin V1b Receptors using SSR-149415, a nonpeptide V1b Receptor ligand
American journal of physiology. Regulatory integrative and comparative physiology, 2007Co-Authors: Claudine Serradeille Gal, Jean Wagnon, Marc Pascal, Danièle Raufaste, Sylvain Derick, Jörg Blankenstein, John Allen, Brigitte Pouzet, Maria A. VenturaAbstract:[3H]SSR-149415 is the first tritiated nonpeptide Vasopressin V1b Receptor (V1bR) antagonist ligand. It was used for studying rodent (mouse, rat, hamster) and human V1bR from native or recombinant o...
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an overview of ssr149415 a selective nonpeptide Vasopressin V1b Receptor antagonist for the treatment of stress related disorders
Cns Drug Reviews, 2006Co-Authors: Claudine Serradeille Gal, Jean Wagnon, Guy Griebel, Bernard Tonnerre, Richard Roux, Georges Garcia, Alain AulombardAbstract:Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central Vasopressin V1b Receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active Vasopressin V1b Receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V1b Receptors and displays a highly selective profile with regard to a large number of Receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V1b Receptor activation by AVP, such as intracellular Ca2+ increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.
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An Overview of SSR149415, a Selective Nonpeptide Vasopressin V1b Receptor Antagonist for the Treatment of Stress‐Related Disorders
CNS drug reviews, 2006Co-Authors: Claudine Serradeille Gal, Jean Wagnon, Guy Griebel, Bernard Tonnerre, Richard Roux, Georges Garcia, Aulombard AlainAbstract:Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central Vasopressin V1b Receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active Vasopressin V1b Receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V1b Receptors and displays a highly selective profile with regard to a large number of Receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V1b Receptor activation by AVP, such as intracellular Ca2+ increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.
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Non-peptide Vasopressin V1b Receptor antagonists as potential drugs for the treatment of stress-related disorders.
Current pharmaceutical design, 2005Co-Authors: Guy Griebel, Claudine Serradeille Gal, Jeanne Stemmelin, Philippe SoubrieAbstract:Since Vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active nonpeptide V1b Receptor antagonist, SSR149415, opened a new era for examining the role of Vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V1b Receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V1b Receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.
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Chapter 4.2 – Nonpeptide Vasopressin V1b Receptor antagonists
Handbook of Stress and the Brain - Part 2: Stress: Integrative and Clinical Aspects, 2005Co-Authors: Guy Griebel, Claudine Serradeille GalAbstract:Abstract Arginine Vasopressin (AVP) is critical for adaptation of the hypothalamo–pituitary–adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF. This observation, taken together with the identification of AVP Receptors (e.g. V 1b ) in limbic structures has led to the idea that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of an orally active nonpeptide V 1b Receptor antagonist has allowed to verify this hypothesis. Studies in animals have shown that the V 1b Receptor antagonist, SSR149415, is able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like effects of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. While the latter were active in a wide range of anxiety models, the AVP antagonist showed clear-cut effects only in particularly stressful situations. Moreover, SSR 149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. heart rate) responses following acute stress exposure in rats. It is noteworthy that SSR149415 was devoid of central effects not related to emotionality. Altogether, these findings suggest that blockade of central V 1b Receptors may represent a new therapeutic strategy for the treatment of depression and some forms of anxiety disorders.
Greti Aguilera - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Vasopressin V1b Receptor translation by upstream open reading frames in the 5'-untranslated region.
Journal of neuroendocrinology, 2007Co-Authors: Cristina Rabadan-diehl, Simona Volpi, Alfredo Martínez, Sivan Subburaju, Greti AguileraAbstract:The 5'-UTR of the Vasopressin V1b Receptor (V1bR) mRNA contains small open reading frames (ORF) located upstream (u) of the main ORF encoding the V1bR. The ability of the three proximal uORFs to be translated into peptides and their influence on V1bR translation was examined using fusion constructs of uORFs and V5 epitope, or ATG/ATA uORF mutations in the V1bR cDNA. In vitro translation and western blot analysis after transfection of uORF1-V5 or uORF2-V5 into cells revealed that uORF1 can be translated. As predicted by computer analysis, in vitro translation using a rabbit reticulocyte/canine microsome system, immunohistochemistry and western blot in membranes of transfected cells with uORF1-V5 revealed translocation of the uORF1 peptide into membrane fractions. In vitro translation of V1bR cDNA with mutations of the two uORFs proximal to the initiating methionine, uORFs 1 and 2 (Mut 1-2), or uORF2 (Mut 2) showed significantly increased translation of a 46 kDa band corresponding to the V1bR, compared with wild-type (WT) V1bR, an effect that was attenuated by cotranslation of uORF1-V5. Consistently, VP-induced inositol phosphate formation was higher in Chinese hamster ovay cells transfected with Mut 1-2 than with WT V1bR. Immunohistochemical and western blot analysis, using an antibody against uORF1, revealed peptide immunoreactivity in rat pituitary but not in liver. Pituitary uORF immunoreactivity increased following glucocorticoid administration. The present study shows that uORFs in the 5'-UTR of the V1bR mRNA inhibit V1bR translation, and suggests that translation of a 38-amino acid membrane peptide encoded by uORF1 exerts tonic inhibition of V1bR translation.
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Translational regulation of the Vasopressin V1b Receptor involves an internal ribosome entry site.
Molecular endocrinology (Baltimore Md.), 2003Co-Authors: Cristina Rabadan-diehl, Simona Volpi, Maria Nikodemova, Greti AguileraAbstract:Posttranscriptional mechanisms play an important role regulating pituitary levels of Vasopressin V1b Receptors (V1bR) during adaptation to stress. This study investigates the involvement of an internal ribosome entry site (IRES) in the 5′untranslated region (5′UTR) on V1bR translation. Transfection of bicistronic luciferase constructs into MCF-7 cells showed marked increases in translation of the second cistron after insertion of a 499-bp fragment of the V1bR 5′UTR in the intercistronic region, independently of cap-mediated translation, indicating the presence of IRES activity. IRES-mediated translation was potentiated by the protein kinase C activators, 12-O-tetradecanoylphorbol 13-acetate (PMA) and bryostatin 1, and appears to involve phosphorylation of amino terminus of eIF4G. In Chinese hamster ovary cells transfected with pV1bR-green fluorescent protein (pV1bR-GFP), PMA increased V1bR-GFP protein levels when cap-mediated translation was inhibited by rapamycin. The effect of PMA was due to increased t...
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Transcriptional and post-transcriptional mechanisms regulating the rat pituitary Vasopressin V1b Receptor gene
Journal of molecular endocrinology, 2003Co-Authors: Greti Aguilera, Simona Volpi, Cristina Rabadan-diehlAbstract:The number of V1b Vasopressin Receptors (V1bR) in the anterior pituitary plays an important role during adaptation of the hypothalamic-pituitary-adrenal axis to stress in rats. Regulation of V1bR expression involves transcriptional and translational mechanisms. One of the elements mediating transcriptional activation of the rat V1bR gene is a long stretch of GAGA repeats (GAGA box) in the promoter located near the transcription start point capable of binding a protein complex of 127 kDa present in pituitary nuclear extracts. There is a lack of correlation between changes in V1bR mRNA and the number of VP binding sites, suggesting that V1bR expression depends on the efficiency of V1b R mRNA translation into protein. Two mechanisms by which the 5' untranslated region (5'-UTR) of the rat V1bR mRNA can mediate either inhibition or activation of V1bR mRNA translation have been identified. First, upstream open reading frames (ORF) present in the 5'-UTR repress translation of the major ORF encoding the V1b Receptor, and secondly, an internal ribosome entry site (IRES) activates V1bR translation. Stimulation of IRES activity through protein kinase C-mediated pathways results in V1bR mRNA translation increasing V1bR protein levels. The existence of multiple loci of regulation for the V1bR at transcriptional and translational levels provides a mechanism to facilitate plasticity of regulation of the number of pituitary Vasopressin Receptors according to physiological demand.
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G PROTEIN-COUPLED Receptor SIGNALLING IN NEUROENDOCRINE SYSTEMS Transcriptional and post-transcriptional mechanisms regulating the rat pituitary Vasopressin V1b Receptor gene
2003Co-Authors: Greti Aguilera, Simona Volpi, C Rabadan-diehlAbstract:The number of V1b Vasopressin Receptors (V1bR) in the anterior pituitary plays an important role during adaptation of the hypothalamic–pituitary–adrenal axis to stress in rats. Regulation of V1bR expression involves transcriptional and translational mechanisms. One of the elements mediating transcriptional activation of the rat V1bR gene is a long stretch of GAGA repeats (GAGA box) in the promoter located near the transcription start point capable of binding a protein complex of 127 kDa present in pituitary nuclear extracts. There is a lack of correlation between changes in V1bR mRNA and the number of VP binding sites, suggesting that V1bR expression depends on the efficiency of V1b R mRNA translation into protein. Two mechanisms by which the 5′ untranslated region (5′-UTR) of the rat V1bR mRNA can mediate either inhibition or activation of V1bR mRNA translation have been identified. First, upstream open reading frames (ORF) present in the 5′-UTR repress translation of the major ORF encoding the V1b Receptor, and secondly, an internal ribosome entry site (IRES) activates V1bR translation. Stimulation of IRES activity through protein kinase C-mediated pathways results in V1bR mRNA translation increasing V1bR protein levels. The existence of multiple loci of regulation for the V1bR at transcriptional and translational levels provides a mechanism to facilitate plasticity of regulation of the number of pituitary Vasopressin Receptors according to physiological demand.
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Transcriptional Regulation of the Pituitary Vasopressin V1b Receptor Involves a GAGA-binding Protein
The Journal of biological chemistry, 2002Co-Authors: Simona Volpi, Cristina Rabadan-diehl, Niamh X. Cawley, Greti AguileraAbstract:Abstract The role of CT repeats (inverted GAGA box) in the rat Vasopressin V1b Receptor (V1bR) promoter in the transcriptional regulation of this gene was studied in H32 hypothalamic cells, which express endogenous V1bR. Transfection of a 2.5-kb V1bR fragment (2161 bp upstream and 377 bp downstream of the proximal transcriptional start point) into a luciferase vector (V1bRp2.5-Luc) results in promoter activity in these cells. The 670-bp proximal promoter fragment containing the GAGA box showed maximal promoter activity, whereas deletion of the GAGA box abolished transcription.Drosophila GAGA-binding protein increased V1bR promoter activity by 11-fold when cotransfected with V1bRp2.5-Luc and increased endogenous V1bR expression. Electrophoretic mobility shift assay showed specific binding of pituitary nuclear extracts to radiolabeled GAGA oligonucleotides, which increased following restraint stress in rats, a condition associated with V1bR up-regulation. DNA-binding activity involved a protein complex because it was abolished by deoxycholate. Size-exclusion column chromatography showed a complex of 127 kDa, which dissociated into ∼70-kDa components after deoxycholate/Nonidet P-40 treatment. This study demonstrates that interactions of GAGA-binding proteins with the GAGA box of the V1bR promoter activate V1bR gene expression and provides a potential mechanism for physiological regulation of V1bR transcription.
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Vasopressin V1b Receptor Antagonists as Potential Antidepressants.
The international journal of neuropsychopharmacology, 2021Co-Authors: Shigeyuki ChakiAbstract:Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-Vasopressin (AVP) is one of primary factors in HPA axis regulation under stress situations, and AVP and its Receptor subtype (V1b Receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1b Receptor antagonists have been synthesized, and the efficacies of some V1b Receptor antagonists have been investigated in both animals and humans. V1b Receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least two V1b Receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1b Receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1b Receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1b Receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.
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efficacy and safety of ts 121 a novel Vasopressin V1b Receptor antagonist as adjunctive treatment for patients with major depressive disorder a randomized double blind placebo controlled study
Journal of Psychiatric Research, 2020Co-Authors: Makoto Kamiya, Michihiko Iijima, Shigeyuki Chaki, Helene D Sabia, Julie Marella, Maurizio Fava, Charles B Nemeroff, Hideo Umeuchi, Izumi NishinoAbstract:Abstract Vasopressin 1B (V1b) Receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V1b Receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V1b Receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.
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Antidepressant and anxiolytic profiles of newly synthesized arginine Vasopressin V1b Receptor antagonists: TASP0233278 and TASP0390325
British journal of pharmacology, 2014Co-Authors: Michihiko Iijima, Toshiharu Shimazaki, Takao Yoshimizu, K Tokugawa, Kenichi Fukumoto, Shinsuke Kurosu, T Kuwada, Yoshinori Sekiguchi, Shigeyuki ChakiAbstract:Background and Purpose Vasopressin V1b Receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine Vasopressin Receptor 1B (V1b Receptor) antagonists, TASP0233278 and TASP0390325. Experimental Approach We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models. Key Results Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1b Receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1b Receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats). Conclusion TASP0233278 and TASP0390325 are potent and orally active V1b Receptor antagonists with antidepressant and anxiolytic activities in rodents.
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The pituitary mediates the anxiolytic-like effects of the Vasopressin V1b Receptor antagonist, SSR149415, in a social interaction test in rats.
European Journal of Pharmacology, 2006Co-Authors: Toshiharu Shimazaki, Michihiko Iijima, Shigeyuki ChakiAbstract:Abstract A Vasopressin V 1B Receptor antagonist has been shown to exhibit anxiolytic effects in a variety of animal models of anxiety. In the present study, we examined the involvement of the pituitary in the anxiolytic effects of a Vasopressin V 1B Receptor antagonist by conducting a social interaction test in rats. In the sham-operated rats, both the Vasopressin V 1B Receptor antagonist SSR149415 and the benzodiazepine chlordiazepoxide significantly increased the social behavior of a pair of unfamiliar rats, and the blood adrenocorticotropic hormone levels were markedly increased during the social interaction test. Hypophysectomy also increased the length of time that the animals engaged in social behavior to the same extent as that observed after treatment of the sham-operated rats with anxiolytics. However, while chlordiazepoxide further increased the duration of social interaction in the hypophysectomized rats, the anxiolytic effects of SSR149415 was no longer observed in these animals. These results suggest that the anxiolytic effects of the Vasopressin V 1B Receptor antagonist in the social interaction test are mediated through blockade of the Vasopressin V 1B Receptor in the pituitary.
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ATC0175: an orally active melanin-concentrating hormone Receptor 1 antagonist for the potential treatment of depression and anxiety.
CNS drug reviews, 2006Co-Authors: Shigeyuki Chaki, Junichi Yamaguchi, Hisaharu Yamada, William Thomsen, Thuy-anh Tran, Graeme Semple, Yoshinori SekiguchiAbstract:Melanin-concentrating hormone (MCH) has been implicated in a variety of physiological events. Recent studies clearly suggest that MCH plays an important role in the regulation of stress and emotion. To date, two Receptor subtypes of MCH (MCH1R and MCH2R) have been identified. MCH1R has been suggested to mediate most of the physiological functions of MCH. Recently, we synthesized an orally active, nonpeptidic antagonist of MCH1R, N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride (ATC0175). This compound is a potent antagonist with a high affinity for MCH1R and additional affinities for 5-HT1A and 5-HT2B Receptors. The Receptor binding and the functional assay (MCH-induced increase in [Ca2+]i) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs. ATC0175 exhibited anxiolytic effects in numerous animal models of anxiety including the elevated plus-maze test, social interaction test, stress-induced hyperthermia and maternal separation-induced vocalization. Like with other stress-related peptide Receptor antagonists, such as antagonists of corticotropin-releasing factor or Vasopressin V1b Receptor antagonists, anxiolytic effects of ATC0175 were more pronounced in models containing a stress component. ATC0175 also exhibited antidepressant effects in the forced swimming test. ATC0175 increased swimming performance without altering climbing behavior, as observed with selective serotonin reuptake inhibitors. ATC0175 has adequate ADME profile (reasonable oral bioavailability and brain penetration) and potent oral activity in animal models. In contrast, ATC0175 did not affect spontaneous locomotor activity, hexobarbital-induced sleeping time and did not impair rotarod performance. Thus, ATC0175 may be devoid of unwanted central nervous system side effects, which are sometimes observed with current medications. In addition, ATC0175 was well tolerated in rat repeated toxicity study, and had no genotoxic liability. Therefore, ATC0175 has the potential to be effective in the treatment of patients with depression and/or anxiety disorders.