The corticotropin-releasing factor receptor: a novel target for the treatment of depression and anxiety-related disorders

The 41-amino acid peptide corticotropin releasing factor (CRF) is a major modulator of the mammalian stress response. Upon stressful stimuli, it binds to the corticotropin releasing factor receptor 1 (CRF1R), a typical member of the class-B G-protein-coupled receptors (GPCRs) and a prime target in the treatment of mood disorders. To chemically probe the molecular interaction of CRF with the transmembrane domain of its cognate receptor, we developed a high-throughput conjugation approach that mimics the natural activation mechanism of class-B GPCRs. An acetylene-tagged peptide library was synthesized and conjugated to an azide-modified high-affinity carrier peptide derived from the CRF C-terminus using copper-catalyzed dipolar cycloaddition. The resulting conjugates reconstituted potent agonists and were tested in situ for activation of the CRF1 receptor in a cell-based assay. By use of this approach we (i) defined the minimal sequence motif that is required for full receptor activation, (ii) identified the critical functional groups and structure–activity relationships, (iii) developed an optimized, highly modified peptide probe with high potency (EC50 = 4 nM) that is specific for the activation domain of the receptor, and (iv) probed the behavioral role of CRF receptors in living mice. The membrane recruitment by a high-affinity carrier enhanced the potency of the tethered peptides by >4 orders of magnitude and thus allowed the testing of very weak initial fragments that otherwise would have been inactive on their own. As no chromatography purification of the test peptides was necessary, a substantial increase in screening throughput was achieved. Importantly, the peptide conjugates can be used to probe the endogenous receptor in its native environment in vivo.

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“…and CRH 2 receptors (Grigoriadis 2005;Yamada et al 2004). X = cyclohexyl alanine; f = Dphenylalanine; EAEK = lactam bridge.…”

Section: Both Crh and Ucn Have High Affinities For The Crh-binding Prmentioning

confidence: 99%

Biomimetic Screening of Class-B G Protein-Coupled Receptors

et al. 2011

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“…Based on the evidence for CRF dysfunction in depression and anxiety patients, CRF 1 and CRF 2 receptors, as well as the CRF-BP, have been proposed as pharmacotherapeutic targets for depression and anxiety disorders (Arborelius et al, 1999;Grigoriadis, 2005;Valdez et al, 2005;Van Den Eede et al, 2005). Potent, orally active small molecule CRF 1 antagonists have now been developed and are ready for human investigation (Dyck et al, 2005).…”

Section: Anxietymentioning

confidence: 99%

“…The literature on functioning of the HPA axis in PTSD is more controversial and conflicted. Some experts find reasonably consistent evidence of hypocortisolemia and enhanced HPA axis negative feedback (e.g., Yehuda, 2002), although these effects have not been consistently replicated in other studies which report either hypercortisolemia or even normal plasma cortisol in the presence of elevated CSF levels of cortisol (e.g., Baker et al, 2005).Based on the evidence for CRF dysfunction in depression and anxiety patients, CRF 1 and CRF 2 receptors, as well as the CRF-BP, have been proposed as pharmacotherapeutic targets for depression and anxiety disorders (Arborelius et al, 1999;Grigoriadis, 2005;Valdez et al, 2005;Van Den Eede et al, 2005). Potent, orally active small molecule CRF 1 antagonists have now been developed and are ready for human investigation (Dyck et al, 2005).…”

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confidence: 99%

Role of corticotropin releasing factor in anxiety disorders: A translational research perspective

Risbrough

Stein

2006

Hormones and Behavior

211

139

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Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety. KeywordsCRH; CRF; Posttraumatic stress disorder; Anxiety; Panic disorder; Startle Overview of CRF neuroendocrine effects and its effects on G-protein-coupled receptorsCorticotropin releasing factor (CRF; also termed "CRH" for corticotropin releasing hormone) was first described in Science by Vale et al. (1981). They reported the discovery of a hypothesized hypothalamic factor, CRF, a 41 amino acid peptide which selectively and potently activated pituitary corticotropin (or adrenal corticotropin releasing hormone, ACTH) secretion. They predicted that this peptide could be "a key signal in mediating and integrating an organism's endocrine, visceral and behavioral response to stress" (Vale et al., 1981(Vale et al., p. 1397). More than 20 years of subsequent animal research and clinical studies have confirmed this hypothesis, supporting a role for CRF, and its more recently discovered ligand family Urocortin 1, 2 and 3, in anxiety and stress responses Reyes et al., 2001;Spina et al., 1996). In this review, we will focus on the current state of knowledge of CRF system dysregulation in clinical anxiety and discuss future avenues of translational research on the role of CRF in startle phenotypes observed in some anxiety disorders. CRF mediation of the neuroendocrine response to stressIn response to stress, CRF is released from the median eminence of the hypothalamus, where it subsequently binds to receptors at the anterior pituitary and increases ACTH release into the * Corresponding author. 8950 Villa La Jolla Drive, Suite B-218, La Jolla, CA 92037, USA. E-mail address: mstein@ucsd.edu (M.B. Stein). bloodstream. ACTH consequently acts at the adrenal cortex to facilitate release of glucocorticoids such as cortisol. This system, known as the hypothalamic-pituitary-adrenal axis (HPA), is an important component of the response to stress and has been shown to be dysregulated in both anxiety and de...

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“…Urocortin 1 (UCN1) has equal affinity for both receptor subtypes although urocortin 2 and 3 (UCN2 and UCN3) have higher affinity and selectivity for the CRF 2 receptor subtype (Perrin and Vale, 1999;Skelton et al, 2000). There have been many studies, detailing the role of this family of receptors and corresponding ligands in stress-related diseases including anxiety and depression, which has generated a tremendous amount of interest in the development of novel antagonists (Grigoriadis, 2005;Holsboer, 2003;Zorrilla and Koob, 2004).…”

Section: Introductionmentioning

confidence: 99%

High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

Ising

Zimmermann

Kuenzel

et al. 2007

Neuropsychopharmacol

Self Cite

134

101

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There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF 1 antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague-Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF 1 receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic-pituitaryadrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 mg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.

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The corticotropin-releasing factor receptor: a novel target for the treatment of depression and anxiety-related disorders

Cited by 76 publications

References 251 publications

Biomimetic Screening of Class-B G Protein-Coupled Receptors

Biomimetic Screening of Class-B G Protein-Coupled Receptors

Role of corticotropin releasing factor in anxiety disorders: A translational research perspective

High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

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