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A Corticotropin-Releasing Hormone Antagonist is a specific type of receptor antagonist that blocks the receptor sites for Corticotropin-releasing hormone (also known as Corticotropin-releasing factor (CRF)), thereby blocking the consequent secretions of ACTH and cortisol.

There are four subtypes of this receptor known at present, defined as CRF-1, CRF-2a, CRF-2b, and CRF-2g. Three of these receptors are expressed only in the brain, CRF-1 in the cortex and cerebrum, CRF-2a in the lateral septum and hypothalamus, and CRF-2g in the amygdala. CRF-2b is expressed in the choroid plexus and cerebral arterioles in the brain, but is expressed mainly peripherally on the heart and skeletal muscle tissue.[1]

The main research into CRF antagonists to date has focused on antagonists selective for the CRF-1 subtype. Several antagonists for this receptor have been developed and are widely used in research, with the best-known agents being the selective CRF-1 antagonist antalarmin and a newer drug pexacerfont, although several other ligands for this receptor are used in research, such as LWH-234, CP-154,526, NBI-27914 and R-121,919. Antagonists acting at CRF-2 have also been developed, such as the peptide Astressin-B,[2] but so far no highly selective agents for the different CRF-2 subtypes are available.

It's been shown that "the effect of footshock on reinstatement of alcohol seeking is block by systemic, ventricular, or intra-median raphe injections of CRF receptor antagonists."[3][4]

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References

  1. ^ McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. Current Pharmaceutical Design. 1999 May; 5(5):289-315.
  2. ^ Vulliemoz NR, Xiao E, Xia-Zhang L, Rivier J, Ferin M. Astressin B, a non selective CRH receptor antagonist, prevents the inhibitory effect of Ghrelin on LH pulse frequency in the ovariectomized rhesus monkey. Endocrinology. 2007 Dec 6.
  3. ^ Lê AD, Harding S, Watchus W, Juzytsch W, Shalev U, Shaham Y (2000) The role of corticotropin-releasing factor in stress-in- duced relapse to alcohol-seeking behavior in rats. Psychophar- macology 150:317–324
  4. ^ Lê AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2002) The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J Neurosci 22:7844–7849


Template:Neuropeptidergics

Category:Corticotropin-releasing hormone Category:CRF-1 antagonists


Ruth Draft:

A Corticotropin-Releasing Hormone Antagonist (CRH antagonist) is a specific type of receptor antagonist that blocks the receptor sites for Corticotropin-releasing hormone (also known as Corticotropin-releasing factor (CRF)), which synchronizes the behavioral, endocrine, autonomic, and immune responses to stress by controling the hypothalamic-pituitary-adrenal axis (HPA Axis) [1].

CRH Receptor Subtypes

There are four subtypes of the CRH receptor known at present, defined as CRF-1, CRF-2a, CRF-2b, and CRF-2g. Three of these receptors are expressed only in the brain, CRF-1 in the cortex and cerebrum, CRF-2a in the lateral septum and hypothalamus, and CRF-2g in the amygdala. CRF-2b is expressed in the choroid plexus and cerebral arterioles in the brain, but is expressed mainly peripherally on the heart and skeletal muscle tissue.[2] Extensive research has shown that overactivity in the brain CRF-CRF1 signaling system contributes to the onset of anxiety disorders and depression. It's been hypothesized that patients with clinical conditions that are causally related to HPA hyperactivity, including major depression and post-traumatic stress disorders, may benefit from CRH receptor antagonist treatment. CRH antagonists are believed to work by blocking the consequent secretions of ACTH and cortisol that occur following activation of CRH. There is increased clinical interest in CRH receptor antagonists that can cross the blood-brain barrier for the treatment of depression and anxiety, along with other conditions related to HPA hyperactivity, including treatment of functional gastrointestinal disorders such as irritable bowel syndrome [3][4].

CRH Receptor Antagonists Research

Peptide-based synthetic CRH receptor antagonists have been researched, but as they cannot pass through the blood-brain barrier, clinical research applications seem unlikely at this point[5], while non-peptidic selective CRH-R1 receptor antagonists have been both researched and synthesized with moderate levels of success. The majority of these antagonists are comprised of a general pharmacophore that is consistent in most research experiments, with minor alterations [6]. The main research into clinical CRF antagonists has focused on antagonists selective for the CRF-1 subtype, which is expressed in the cortex and cerebrum. Several antagonists for this receptor have been developed and are widely used in research, with the best-known agents being the selective CRF-1 antagonist antalarmin and a newer drug pexacerfont. A recent human trial disappointingly found that pexacerfont did no better than a placebo in alleviating the symptoms of General Anxiety Disorder [7], though additional research is still needed. Several other ligands for the CRF-1 receptor antagonist used in research include LWH-234, CP-154,526, NBI-27914 and R-121,919. A small human clinical trial showed that CRF1 antagonist R-121,919 is effective in reducing depression and anxiety scores in patients with major depression[8][9], with no adverse side effects. Antagonists acting at CRF-2 have also been developed, such as the peptide Astressin-B,[10] but so far no highly selective agents for CRF-2 subtypes are available. There is an increased interest in research on the combinational treatment of CRF-1 and CRF-2 antagonists, along with concurrent SSRI treatment [11] for the treatment of anxiety disorders.

Other CRH Receptor Antagonist Applications

CRH receptor antagonists also have other clinical applications aside from the traditional concept of treating depression and anxiety. CRH receptor antagonists could potentially be used as adjunct agents to retinol and flavonoids to inhibit mast cell activation in chronic cutaneous inflammatory skin diseases like psoriasis and atopic dermatitis, the symptoms of which are often further exacerbated by stress and subsequent HPA activation [12]. There is also hope that CRH receptor antagonists could be useful in the treatment of psychosocial growth retardation, euthyroid sick syndrome, and peripheral inflammatory disorders involving mast cell degranulation, such as stress-induced asthma and urticaria[13]. More research on CRH receptor antagonists, as well as the mechanisms behind them, needs to be completed before further clinical aspirations can be properly considered.

  1. ^ ZOUMAKIS, E., RICE, K. C., GOLD, P.W. and CHROUSOS, G. P. (2006), Potential Uses of Corticotropin-Releasing Hormone Antagonists. Annals of the New York Academy of Sciences, 1083: 239–251. doi: 10.1196/annals.1367.021
  2. ^ McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. Current Pharmaceutical Design. 1999 May; 5(5):289-315.
  3. ^ Taché Y. Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology? Gut. 2004;53(7):919-921. doi:10.1136/gut.2003.036400
  4. ^ Reul JMHM, Holsboer F. On the role of corticotropin-releasing hormone receptors in anxiety and depression. Dialogues in Clinical Neuroscience. 2002;4(1):31-46.
  5. ^ ZOUMAKIS, E., RICE, K. C., GOLD, P.W. and CHROUSOS, G. P. (2006), Potential Uses of Corticotropin-Releasing Hormone Antagonists. Annals of the New York Academy of Sciences, 1083: 239–251. doi: 10.1196/annals.1367.021
  6. ^ ZOUMAKIS, E., RICE, K. C., GOLD, P.W. and CHROUSOS, G. P. (2006), Potential Uses of Corticotropin-Releasing Hormone Antagonists. Annals of the New York Academy of Sciences, 1083: 239–251. doi: 10.1196/annals.1367.021
  7. ^ Coric, V; Feldman, HH; Oren, DA; Shekhar, A; Pultz, J; Dockens, RC; Wu, X; Gentile, KA; Huang, SP; Emison, E; Delmonte, T; D'Souza, BB; Zimbroff, DL; Grebb, JA; Goddard, AW; Stock, EG (May 2010). "Multicenter, Randomized, Double-Blind, Active Comparator and Placebo-Controlled Trial of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Generalized Anxiety Disorder". Depression and Anxiety. 27 (5): 417–25. doi:10.1002/da.20695. PMID 20455246. Retrieved 16 July 2016.
  8. ^ Taché Y. Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology? Gut. 2004;53(7):919-921. doi:10.1136/gut.2003.036400
  9. ^ https://www.ncbi.nlm.nih.gov/pubmed/14563384
  10. ^ Vulliemoz NR, Xiao E, Xia-Zhang L, Rivier J, Ferin M. Astressin B, a non selective CRH receptor antagonist, prevents the inhibitory effect of Ghrelin on LH pulse frequency in the ovariectomized rhesus monkey. Endocrinology. 2007 Dec 6.
  11. ^ Coric, V; Feldman, HH; Oren, DA; Shekhar, A; Pultz, J; Dockens, RC; Wu, X; Gentile, KA; Huang, SP; Emison, E; Delmonte, T; D'Souza, BB; Zimbroff, DL; Grebb, JA; Goddard, AW; Stock, EG (May 2010). "Multicenter, Randomized, Double-Blind, Active Comparator and Placebo-Controlled Trial of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Generalized Anxiety Disorder". Depression and Anxiety. 27 (5): 417–25. doi:10.1002/da.20695. PMID 20455246. Retrieved 16 July 2016.
  12. ^ ZOUMAKIS, E., RICE, K. C., GOLD, P.W. and CHROUSOS, G. P. (2006), Potential Uses of Corticotropin-Releasing Hormone Antagonists. Annals of the New York Academy of Sciences, 1083: 239–251. doi: 10.1196/annals.1367.021
  13. ^ Habib, Kamal E., et al. "Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates." Proceedings of the National Academy of Sciences 97.11 (2000): 6079-6084.
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