Corticotropin-releasing hormone antagonist

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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 controlling the hypothalamic-pituitary-adrenal axis (HPA axis). [1] CRH antagonists thereby block the consequent secretions of ACTH and cortisol due to stress, among other effects.

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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 and lowering the stress-induced rise of CRH in CSF. 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 irritable bowel syndrome, which is exacerbated by stress. [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, [1] while non-peptidic selective CRH-R1 receptor antagonists have been both researched and synthesized with moderate levels of success. The majority of these antagonists consist of a general pharmacophore that is consistent in most research experiments, with minor alterations. [1] 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, due to its heightened role in HPA hyperactivity. 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, [5] though additional research is still needed. In monkeys, antalarmin has been successful in lowering the stress-induced CRF rise in CSF, suppressing anxiety-associated behaviors, and increased exploratory behavior in a stressful situation, but human trials are necessary to comprehend the clinical efficacy of antalarmin. [6] 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 30 days of treatment with CRF1 antagonist R-121,919 was effective in lowering depression and anxiety scores in both male and female patients who had suffered a major depressive episode, [3] [7] with no adverse side effects. Antagonists acting at CRF-2 have also been developed, such as the peptide Astressin-B, [8] 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, [5] for the treatment of anxiety disorders.

Other CRH receptor antagonist clinical applications

CRH receptor antagonists also have other possible clinical applications aside from the traditional concept of treating depression and anxiety. CRH receptor antagonists could potentially be used as co-treatments with retinol and flavonoids in order to alleviate the symptoms of chronic inflammatory skin diseases like psoriasis and atopic dermatitis, which are often further exacerbated by HPA activation due to stress. [1] There is also hope that CRH receptor antagonists could be useful in the treatment of a range of clinical disorders associated with abnormal stress responses, such as psychosocial growth retardation, euthyroid sick syndrome, stress-induced asthma, and psychogenic impotence. [6] Further research on CRH-1 and CRH-2 receptor antagonists, as well as the mechanisms behind them, needs to be completed before further clinical aspirations can be properly considered.

Related Research Articles

Corticotropin-releasing hormone

Corticotropin-releasing hormone (CRH) is a peptide hormone involved in the stress response. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene. Its main function is the stimulation of the pituitary synthesis of ACTH, as part of the HPA Axis.

Hypothalamic–pituitary–adrenal axis Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands.

Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone, urotensin-I, urocortin, and sauvagine. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRH forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as prohormones.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.

Neuropeptide Y

Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the mammalian central nervous system, which consists of the brain and spinal cord. It is secreted alongside other neurotransmitters such as GABA and glutamate. 

Vasopressin receptor 1B

Vasopressin V1b receptor (V1BR) also known as vasopressin 3 receptor (VPR3) or antidiuretic hormone receptor 1B is a protein that in humans is encoded by the AVPR1B gene.

Urocortin

Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.

Urocortin 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family.

Neurokinin A Chemical compound

Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.

Corticotropin-releasing hormone receptors (CRHRs), also known as corticotropin-releasing factor receptors (CRFRs) are a G protein-coupled receptor family that binds corticotropin-releasing hormone (CRH). There are two receptors in the family, designated as type 1 and 2, each encoded by a separate gene.

Corticotropin-releasing hormone receptor 1

Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name. In humans, CRF1 is encoded by the CRHR1 gene.

Corticotropin-releasing hormone receptor 2

Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF2, that is encoded by the CRHR2 gene and occurs on the surfaces of some mammalian cells. CRF2 receptors are type 2 G protein-coupled receptors for corticotropin-releasing hormone (CRH) that are resident in the plasma membranes of hormone-sensitive cells. CRH, a peptide of 41 amino acids synthesized in the hypothalamus, is the principal neuroregulator of the hypothalamic-pituitary-adrenal axis, signaling via guanine nucleotide-binding proteins (G proteins) and downstream effectors such as adenylate cyclase. The CRF2 receptor is a multi-pass membrane protein with a transmembrane domain composed of seven helices arranged in a V-shape. CRF2 receptors are activated by two structurally similar peptides, urocortin II, and urocortin III, as well as CRH.

Antalarmin Chemical compound

Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.

Pexacerfont

Pexacerfont (INN, previously known as BMS-562,086) is a drug developed by Bristol-Myers Squibb which acts as a CRF1 antagonist.

CP-154,526 Chemical compound

CP-154,526 is a potent and selective antagonist of the corticotropin releasing hormone receptor 1 developed by Pfizer.

Verucerfont

Verucerfont (GSK-561,679) is a drug developed by GlaxoSmithKline which acts as a CRF-1 antagonist. Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress, and activates the two corticotropin-releasing hormone receptors CRH-1 and CRH-2. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress.

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.

Major depressive disorder is heavily influenced by environmental and genetic factors. These factors include epigenetic modification of the genome in which there is a persistent change in gene expression without a change in the actual DNA sequence. Genetic and environmental factors can influence the genome throughout a life; however, an individual is most susceptible during childhood. Early life stresses that could lead to major depressive disorder include periodic maternal separation, child abuse, divorce, and loss. These factors can result in epigenetic marks that can alter gene expression and impact the development of key brain regions such as the hippocampus. Epigenetic factors, such as methylation, could serve as predictors for the effectiveness of certain antidepressant treatments. Currently, antidepressants can be used to stabilize moods and decrease global DNA methylation levels, but they could also be used to determine the risk of depression caused by epigenetic changes. Identifying gene with altered expression could result in new antidepressant treatments.

Emicerfont

Emicerfont (GW-876,008) is a drug developed by GlaxoSmithKline which acts as a CRF-1 antagonist. Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress, and activates the two corticotropin-releasing hormone receptors: CRF1 and CRF2. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress.

References

  1. 1 2 3 4 Zoumakis E, Rice KC, Gold PW, Chrousos GP (November 2006). "Potential uses of corticotropin-releasing hormone antagonists". Annals of the New York Academy of Sciences. 1083 (1): 239–51. Bibcode:2006NYASA1083..239Z. doi:10.1196/annals.1367.021. PMID   17148743. S2CID   7731338.
  2. ↑ McCarthy JR, Heinrichs SC, Grigoriadis DE (May 1999). "Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications". Current Pharmaceutical Design. 5 (5): 289–315. PMID   10213797.
  3. 1 2 Taché Y (July 2004). "Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology?". Gut. 53 (7): 919–21. doi:10.1136/gut.2003.036400. PMC   1774121 . PMID   15194633.
  4. ↑ Reul JM, Holsboer F (March 2002). "On the role of corticotropin-releasing hormone receptors in anxiety and depression". Dialogues in Clinical Neuroscience. 4 (1): 31–46. doi:10.31887/DCNS.2002.4.1/jreul. PMC   3181666 . PMID   22033745.
  5. 1 2 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.
  6. 1 2 Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, Webster EL, Atkinson AJ, Schulkin J, Contoreggi C, Chrousos GP, McCann SM, Suomi SJ, Higley JD, Gold PW (May 2000). "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 of the United States of America. 97 (11): 6079–84. Bibcode:2000PNAS...97.6079H. doi: 10.1073/pnas.97.11.6079 . JSTOR   122584. PMC   18561 . PMID   10823952.
  7. ↑ Künzel HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A, Ising M, Holsboer F (2003). "Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects". Journal of Psychiatric Research. 37 (6): 525–33. doi:10.1016/S0022-3956(03)00070-0. PMID   14563384.
  8. ↑ Vulliémoz NR, Xiao E, Xia-Zhang L, Rivier J, Ferin M (March 2008). "Astressin B, a nonselective corticotropin-releasing hormone receptor antagonist, prevents the inhibitory effect of ghrelin on luteinizing hormone pulse frequency in the ovariectomized rhesus monkey". Endocrinology. 149 (3): 869–74. doi:10.1210/en.2007-1350. PMC   2275354 . PMID   18063681.
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