4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-<i>a</i>]-1,3,5-triazine:  A Potent, Orally Bioavailable CRF<sub>1</sub> Receptor Antagonist

He, Li; Gilligan, Paul J.; Zaczek, Robert; Fitzgerald, Lawrence W.; Mcelroy, J; Shen, H-S. L.; Saye, J; Kalin, Ned H.; Shelton, Steven E.; Christ, David D.; Trainor, George L.; Hartig, Paul

doi:10.1021/jm9904351

Cited by 117 publications

(85 citation statements)

References 32 publications

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“…Thereafter animals were placed in Bollmann cage-type restrainers (Plexiglas cylinders) and were allowed to recover for 30 min before the start of the CRD procedure. The CRD paradigm consisted in ascending graded intensities of phasic isobaric distensions (10,20,40, and 60 mmHg; 20-s duration; 4-min interstimulus interval). VMR to CRD was quantified by measuring EMG activity.…”

Section: Surgery: Implantation Of Electrodes For Electromyography (Emg)mentioning

confidence: 99%

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

Bradesi¹,

Martínez²,

Lao³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bradesi S, Martinez V, Lao L, Larsson H, Mayer EA. Involvement of vasopressin 3 receptors in chronic psychological stressinduced visceral hyperalgesia in rats. Am J Physiol Gastrointest Liver Physiol 296: G302-G309, 2009. First published November 25, 2008 doi:10.1152/ajpgi.90557.2008.-Visceral hypersensitivity and stress have been implicated in the pathophysiology of functional gastrointestinal disorders. We used a selective vasopressin 3 (V 3) receptor antagonist SSR149415 to investigate the involvement of the vasopressin (AVP)/V 3 signaling system in the development of stress-induced visceral hyperalgesia in rats. Rats were exposed to a daily 1-h session of water avoidance stress (WAS) or sham WAS for 10 consecutive days. The visceromotor response to phasic colorectal distension (CRD, 10 -60 mmHg) was assessed before and after stress. Animals were treated daily with SSR149415 (0.3, 1, or 3 mg/kg ip 30 min before each WAS or sham WAS session), with a single dose of SSR149415 (1 mg/kg ip), or the selective corticotropin-releasing factor 1 (CRF 1) antagonist DMP-696 (30 mg/kg po) before CRD at day 11. Effects of a single dose of SSR149415 (10 mg/kg iv) on acute mechanical sensitization during repetitive CRD (12 distensions at 80 mmHg) were also assessed. In vehicle-treated rats, repeated WAS increased the response to CRD, indicating visceral hypersensitivity. Repeated administration of SSR149415 at 1 or 3 mg/kg completely prevented stress-induced visceral hyperalgesia. Similarly, a single dose of DMP-696 or SSR149415 completely blocked hyperalgesic responses during CRD. In contrast, a single dose of SSR149415 did not affect the acute hyperalgesic responses induced by repeated, noxious distension. These data support a major role for V 3 receptors in repeated psychological stress-induced visceral hyperalgesia and suggest that pharmacological manipulation of the AVP/V 3 pathway might represent an attractive alternative to the CRF/CRF 1 pathway for the treatment of chronic stress-related gastrointestinal disorders. corticotropin-releasing factor; DMP-696; functional gastrointestinal disorders; irritable bowel syndrome; SSR149415RECURRENT ABDOMINAL PAIN ASSOCIATED with altered bowel habits and increased perception of physiological and experimental colonic stimuli (visceral hypersensitivity) are characteristic findings in patients with irritable bowel syndrome (IBS) (4). Although the pathophysiological basis of IBS is incompletely understood, epidemiological and experimental data indicate an important role of altered brain-gut interactions in this disorder. For example, many studies have highlighted the importance of certain types of psychological stress in the onset, maintenance, and exacerbation of IBS symptoms (5, 6, 32, 33). Furthermore, higher levels of anxiety, symptom-related anxiety, and comorbidity with anxiety disorders or depression are common in patients with IBS (32,33,49). Recent brain imaging studies have shown greater activation of limbic and paralimbic brain regions (including the amygdala) in patient...

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Section: Surgery: Implantation Of Electrodes For Electromyography (Emg)mentioning

confidence: 99%

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

Bradesi¹,

Martínez²,

Lao³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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confidence: 91%

“…The novel phenylpyrimidine, R121919, is similarly active in a "defensive withdrawal" model (Heinrichs et al 2000), and anxiolytic actions have also been claimed for a further pyrollopyrimidine derivative, antalarmin (Deak et al 1999;Fiorino et al 2000). On the other hand, while the pyrazolopyrimidine, DMP904, and the pyrazolotriazine, DMP696, were active in a rat model of "situational anxiety", CP154,526 was not effective in this paradigm He et al 2000).Clearly, the above data are rather disparate, and several reports remain preliminary. To explain contrasting patterns of data regarding the potential anxiolytic actions of non-peptidergic CRF 1 antagonists, inter-species (and inter-strain) differences, as well as procedural variables and the level of stress, have been evoked (Griebel et al 1998;Steckler and Holsboer 1999).…”

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confidence: 97%

“…In contrast, it shows low affinity for CRF 2 ␣ and diverse other classes of receptor (Bakthavatchalam et al 1998;Millan MJ et al, unpublished observations). Further, in vivo, DMP695 shows high bioavailability and is active in a model of situational anxiety in the rat-which is, interestingly, irresponsive to CP154,526 (Bakthavatchalam et al 1998;Gilligan et al 2000;He et al 2000). In the present study, the actions of CP154,526 and DMP695 in plus-maze, Vogel conflict, SI, and conditioned USV procedures, were compared to those of the benzodiazepine (BZD), chlordiazepoxide; the serotonin (5-HT) 1A agonist, flesinoxan; and the 5-HT 2C antagonist, SB242,084 (Barrett and Gleeson 1991;Schreiber and De Vry 1993;Coplan et al 1995;Griebel 1995;Miczek et al 1995;Dekeyne et al 2000;Millan et al 2000a).…”

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confidence: 99%

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Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 A Comparison to Other Classes of Anxiolytic Agent

Millan

2001

Neuropsychopharmacology

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The selective, non-peptidergic corticotropin-releasing factor (CRF) 1 receptor antagonists, CP154,526 and DMP695, dose-dependently increased punished responses of rats in a Vogel conflict test and enhanced social interaction (SI) of rats in an unfamiliarCorticotropin-releasing factor (CRF) plays a crucial role in modulation of the release of adrenocorticotrophic hormone from the anterior pituitary (De Souza 1995). In addition, CRF is broadly distributed throughout the mammalian central nervous system (CNS), being concentrated in corticolimbic regions such as amygdala, hippocampus, and periaqueductal gray (PAG) and frontal cortex (FCX), as well as the locus coeruleus (LC) and dorsal raphe nucleus (DRN), the origin of ascending adrenergic and serotonergic projections, respectively (Sawchenko et al. 1993;Van Bockstaele et al. 1996;Price et al. 1998;Steckler and Holsboer 1999). In line with this organization, independently of the hypothalamocorticotrophic axis, cerebral CRF-containing neurones fulfill an important role in the control of emotional behavior (Adamec and McKay 1993;De Souza 1995;Mitchell 1998;Steckler and Holsboer 1999;Smagin and Dunn 2000), actions expressed via two principal subtypes of CRF receptor, both of which positively couple to adenyl cyclase (Grigoriadis et al. 1996). CRF 1 receptors bind CRF and a related neuropeptide, urocortin, with high affinity whereas CRF 2 receptors display a NO . 4 distinct preference for the latter (Donaldson et al. 1996;Grigoriadis et al. 1996). Of several splice variants of the latter, the CRF 2 ␣ subtype is found predominantly in the rodent CNS, notably in several corticolimbic regions enriched in CRF itself, such as the hippocampus, medial amygdala, septum, olfactory bulb, and raphe nuclei, although species differences in this regard should be pointed out (Chalmers et al. 1995;Sánchez et al. 1999). Studies of mRNA encoding CRF 1 receptors and of the corresponding peptide have established a contrasting pattern of distribution in rats with a predominance of CRF 1 over CRF 2 ␣ sites in anterior pituitary, FCX and basolateral amygdala, as well as high levels in the hippocampus and PAG (Potter et al. 1994;Chalmers et al. 1995;Sánchez et al. 1999;Chen et al. 2000).These observations provide a neuroanatomical substrate for a potential role of CRF 1 and/or CRF 2 receptors in the control of mood (Coplan et al. 1996;Steckler and Holsboer 1999), and, in this regard, there is a diversity of evidence implicating CRF 1 sites in the modulation of anxious states. First, several studies have reported anxiogenic actions of CRF (and urocortin) upon i.c.v. administration (see Steckler and Holsboer, 1999) and similar effects have been seen upon direct introduction into the dorsal PAG (Martins et al. 1997), basolateral amygdala (Sajdyk et al. 1999), and hippocampus (Radulovic et al. 1999), structures possessing a high density of CRF 1 receptors. Second, direct evidence for participation of CRF 1 receptors in anxiogenic actions is derived from studies of antisense probes for their ...

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“…20 For further details on the secondary structure of CRH see previous review. 12 Hypersecretion of CRH in the brain is associated with depression, anxiety-related disorders, and anorexia nervosa, whereas a deficit of CRH in the brain, due to dysfunction of CRH neurons, is associated with Alzheimer's disease, 26,27 Parkinson's disease, 28 and Huntington's disease.…”

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confidence: 99%

The Prevention of Preterm Labour - Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design and Development

Keller¹,

Kirkwood

Morgan³

et al. 2003

MRMC

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The role of the corticotropin releasing hormone in the onset of labour and the subsequent medicinal chemistry implications of CRH antagonists for the prevention of premature birth, and identification of the CRH type 1 receptor as the target for this drug design, are reviewed here. Keywords AbstractThe role of the corticotropin releasing hormone in the onset of labour and the subsequent medicinal chemistry implications of CRH antagonists for the prevention of premature birth, and identification of the CRH type 1 receptor as the target for this drug design, are reviewed here.

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4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: A Potent, Orally Bioavailable CRF₁ Receptor Antagonist

Cited by 117 publications

References 32 publications

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 A Comparison to Other Classes of Anxiolytic Agent

The Prevention of Preterm Labour - Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design and Development

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4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: A Potent, Orally Bioavailable CRF1 Receptor Antagonist

Cited by 117 publications

References 32 publications

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 A Comparison to Other Classes of Anxiolytic Agent

The Prevention of Preterm Labour - Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design and Development

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Product

Resources

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4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: A Potent, Orally Bioavailable CRF₁ Receptor Antagonist