Eur J Endocrinol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1530/eje.1.02259
European Journal of Endocrinology, Vol 155, suppl_1, S85-S91
Copyright © 2006 by European Society of Endocrinology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zoumakis, E
Right arrow Articles by Chrousos, G P
Right arrow Search for Related Content
PubMed
Right arrow Articles by Zoumakis, E
Right arrow Articles by Chrousos, G P
ARTICLE

Corticotropin-releasing hormone receptor antagonists

E Zoumakis, D K Grammatopoulos1 and G P Chrousos

Choremeion Research Laboratory, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, Athens 11527, Greece and 1 Department of Endocrinology and Metabolism, Division of Clinical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK

(Correspondence should be addressed to G P Chrousos; Email: chrousog{at}med.uoa.gr)

Abstract

Corticotropin-releasing hormone (CRH), CRH-related peptides, and CRH receptors play major roles in coordinating the behavioral, endocrine, autonomic, and immune responses to stress. The wide influence of the CRH system on physiological processes in both brain and periphery implicates the respective peptides in the pathophysiology of numerous disorders characterized by dysregulated stress responses. The potential use of CRH antagonists is presently under intense investigation. Selective antagonists have been used experimentally to elucidate the role of CRH-related peptides in disease processes, such as anxiety and depression, sleep disorders, addictive behavior, inflammatory disorders, acute and chronic neurodegeneration, and preterm labor.

Introduction

CRH peptide family

Corticotropin-releasing hormone (CRH) has been identified as the hypothalamic factor controlling the hypothalamic–pituitary–adrenal (HPA) axis in response to stress (1). CRH activates the secretion of pituitary adrenocorticotropic hormone (ACTH), leading to adrenal glucocorticoid production (2, 3). This 41-amino acid (aa) peptide also acts as a neuromodulator, affecting various centers of the brain within the central nervous system (CNS). It is now well established that CRH plays major roles in coordinating the behavioral, endocrine, autonomic, and immune responses to stress.

Three additional endogenous neuropeptides that share significant homology with CRH have been identified, urocortins (Ucns) 1, 2, and 3, each encoded by a different gene (4–8). Non-mammalian peptides, including fish urotensin I and frog sauvagine are also members of CRH-related family of peptides. Ucn 1, is 40 aa long, shares 45% of its sequence with CRH, and is expressed in cell bodies of the Edinger Westphal nucleus (EW), lateral superior olive and supraoptic nucleus in the brain (4), as well as in the gastrointestinal (GI) tract, adipocytes, heart, testis, kidneys, adrenals, pancreas, cardiac myocytes, skin, immune tissues, placenta, and fetal membranes. Ucn possesses hypotensive and appetite-suppressive actions (5), and participates in the inflammation processes (9) and the regulation of cardiac contractility (10). Ucn 2, or stresscopin-related peptide, is a 38 aa peptide expressed in the hypothalamus, brainstem, and spinal cord in the CNS, and human heart, lung, skeletal muscle, stomach, adrenal, and peripheral blood cells (6, 8). Ucn 3, or stresscopin is present in the hypothalamus and medial amygdala in the CNS, and in adipose tissue, heart, muscle, adrenal gland, skin, thyroid, adrenals, ß-cells of the pancreas, spleen, and the muscularis mucosa of the GI tract, in the periphery (6–8, 11). High levels of sequence homology to the non-mammalian peptides sauvagine and urotensin I, isolated from amphibian and teleost fish respectively, have been found.

CRH-binding sites

CRH and CRH-related peptides transduce signals across cells via activation of two types of CRH receptors (Rs), R1 and R2. In addition, the actions of CRH-like peptides are modulated by a soluble high-affinity CRH-binding protein (CRH-BP) (12). CRH-BP is circulating in humans and its physiological role is to control the availability of the free ligand.

CRH-R1{alpha} (18) is a 415 aa protein that contains seven hydrophobic {alpha} helices. Several splice variants have been identified which may encode different isoforms, R1ß, R1c, R1d, R1e, R1f, R1g, and R1h (13–21). CRH-R2 is encoded by a distinct gene and also has three splice mRNAvariants encoding R2{alpha}, R2ß, and R2{gamma} receptor subtypes with unique tissue distributions (20). The two CRH receptor families share 70% homology at the aa level. Recently, a third CRH-R type (CRH-R3) was identified in catfish brain and pituitary. CRH-R1 binds CRH, as well as CRH-related peptides (Ucn, urotensin, and sauvagine, but not Ucns 2 and 3) with equivalent high affinity. CRH-R2 exhibits ligand selectivity and binds Ucn, Ucn2 and Ucn3 with significantly higher binding affinity than the other CRH-like peptides, suggesting that these peptides may be the natural ligands.

CRH receptor antagonists

The first synthetic ligands for CRH receptors were peptide based. As they do not penetrate the blood–brain barrier, no clinical applications have been pursued as yet (22–24).

Over 100 patent claims have been made for non-peptidic, selective CRH-R1 receptor antagonists with clinical potential (25, 26). Interest has been particularly focused on the following compounds: CP-154,526 and its methyl homolog antalarmin, R-121919, R-278995, DMP-696, and DMP-904, SSR-125543A, and NBI-35 965. The majority of these antagonists fit into a general pharmacophore that has the following features (27): a central ring core with a sp2 basic nitrogen that seems to modulate the confirmation of an agonist-binding site, a small alkyl group region, a larger lipophilic side-chain region and an orthogonal aromatic pocket.

Clinical implications of CRH-R antagonists

The availability of multiple CRH-receptor antagonists has led to extensive research focusing on the stress axis and the diseases that may be associated with stress (Table 1Go). Major depression and anxiety, conditions that are related to HPA hyperactivity are good targets for non-peptidic CRH antagonists. Such compounds could be effective in reversing pathological CRH-mediated stress responses, without causing metabolic and other side effects by suppressing the HPA axis (28, 29). Molecules are presently being tested for their anti-anxiety and anti-depression efficacy in phases I and II trials (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1 Potential clinical uses of corticotropin-releasing hormone receptor (CRH-R) antagonists.
 
Experimental and preclinical data also indicate a therapeutic potential of non-peptidic CRH-R1 antagonists for conditions related to neurodegeneration, such as stroke or infantile seizures. Under pathologic conditions, the sites of degeneration have elevated levels of CRH expression (30). In addition, selective CRH-R1 antagonists have been demonstrated to exert anti-ischemic effects in rat models of permanent focal cerebral ischemia and to reverse limbic seizures in neonatal rats (31, 32). Stress is associated with the activation of intracranial mast cells through the sequential action of CRH and sensory neuropeptides (33). This finding could have implications in the treatment of neuroinflammatory disorders, such as migraines and cyclic vomiting syndrome.

The behavioral and physiological manifestations of drug withdrawal and the relapse to drug-taking behavior induced by environmental stressors, seems to be strongly related to the activity of extrahypothalamic brain CRH systems (34). CP-154,526 attenuates stress-induced relapse to drug seeking in rats induced by footshock (35). These results extend previous reports on the role of CRH in reinstatement of drug seeking induced by stressors. Antalarmin reversed the place aversion produced by precipitated opiate withdrawal similar to buprenorphine (36), suggesting a therapeutic potential in opiate dependence.

Dysregulation of the CRH system may contribute to the motivational basis of continued alcohol-seeking behavior during alcohol dependence (37), suggesting a possible effectiveness of CRH-R1 antagonists. Increased CRH activity is a possible mechanism underlying the state of anxiety that develops in alcoholics and leads to mood disturbances and negative affect observed weeks after withdrawal.

Augmented HPA axis function is involved in all aspects of cocaine self-administration. CRH regulates this activation and may be involved in the incentive motivation for the drug and in cue-induced reinstatement of extinguished cocaine-seeking behavior (38). These preclinical data provide evidence for a CRH-based strategy for the treatment of compulsive drug use. CRH-R1 were shown to control the expression of cocaine hyperactivation and sensitization as well as the cocaine-induced relapse behavior, whereas they did not seem to play any role in cocaine discrimination and self-administration (39). These findings suggest that CRH-R1 antagonists should be considered as possible medications in the treatment of cocaine addiction in humans.

The role of the CRH family of neuropeptides in inflammation, as well as experimental data supporting potential therapeutic applications of CRH compounds in various immune-related disorders have recently been reviewed (40). The idea of a functional crosstalk between the neuroendocrine and the immune system was initially conceived by findings showing regulation of CRH secretion in the hypothalamus by the cytokine interleukin (IL)-1ß (41–43). In parallel with the indirect influences of the CRH system on immune function through neuroendocrine activation of the HPA axis, a direct pathway exists through immune tissue-derived local inflammatory actions (44). Application of specific anti-CRH serum or CRH antagonists attenuates the inflammatory reaction in several in vivo models (45, 46). Moreover, CRH endogenous neuropeptides are expressed in different immune cells, including macrophages, lymphocytes, and mast cells in proximity to their receptors and thought to act as autocrine and/or paracrine modulators of inflammatory activity via mutual regulation with cytokines and other mechanisms.

In the mouse spleen, CRH-R1 expression is upregulated by lipopolysaccharide (LPS) stimulation (47) and CRH appears to be necessary for the development of local inflammation induced by carrageenin or turpentine, for basal and inflammation induced IL-6 expression and normal leucocyte function in vitro (45, 48, 49). Synthetic CRH-R1 antagonists attenuate inflammation, indicating a CRH-R1-mediated proinflammatory action. Indeed, chronic blockade of CRH-R1 with systemically administered antalarmin, significantly ameliorated adjuvant-induced arthritis in Lewis (LEW/N) rats, reducing the severity of inflammation in peripheral joints (50). In addition, antalarmin prolonged survival of LPS-induced endotoxin shock and suppressed LPS-induced elevation of the macrophage-derived cytokines tumor necrosis factor (TNF)-{alpha}, IL-1ß, and IL-6 (51), whereas it inhibited stress-induced gastric ulcerogenesis in rats (52).

Increased levels of CRH-related neuropeptides have been found in several conditions presenting with chronic inflammation, including rheumatoid arthritis (53–55), ulcerative colitis (56, 57), Helicobacter pylori-related gastritis (58), endometriosis (59), and Hashimoto’s thyroiditis (60), making them potential indications for specific treatment through CRH receptor blockade.

Recently, CRH-deficient mice were shown to be resistant to experimental autoimmune encephalomyelitis (EAE) in a Th1-specific manner, whereas wild-type EAE mice treated with CRH antagonists showed a decrease in IFN-production by primed T cells in vitro, an effect independent of corticosterone production. These results indicate a proinflammatory role of peripheral CRH in EAE and have implications for the treatment of Th1-mediated diseases such as multiple sclerosis (61).

Based on in vitro and in vivo data, CRH receptor antagonists have been suggested as adjunct agents to retinol and flavonoids for the inhibition of mast cell activation in chronic cutaneous inflammatory skin diseases exacerbated by stress, such as psoriasis and atopic dermatitis (62). CRH induced mast cell degranulation and vascular permeability in the skin (63) and antalarmin inhibited CRH-induced degranulation of mast cells and the secretion of vascular endothelial growth factor (VEGF), which is elevated in psoriasis (64).

Hypothalamic CRH has a direct inhibitory effect on the female reproductive axis by suppression of gonadotropin-releasing hormone secretion (65). Indirectly, glucocorticoids inhibit gonadal axis function at the hypothalamic, pituitary, and uterine levels. CRH and its receptors have been identified in most female reproductive tissues (66, 67), including the ovary, uterus, and placenta. Endometrial implantation sites of the early pregnant rat uterus contain high concentrations of CRH (68). CRH has also been identified in human stromal endometrial cells exhibiting a decidual reaction, and this neuropeptide potentiates the decidualizing effect of progesterone on endometrial stromal cells in vitro (69). In addition, invasive trophoblasts induce apoptosis of activated Fas-expressing human T lymphocytes and this is a CRH-potentiated effect that can be inhibited by antalarmin.

Subcutaneous administration of antalarmin in female rats in the first 6 days of gestation led to a dose-dependent decrease of endometrial implantation sites and live embryos, and markedly diminished endometrial FasL expression (70). It is suggested that CRH participates in the process of both implantation and early pregnancy tolerance in a paradoxic combination of in tandem pro-inflammatory and anti-rejection activities. Therefore, antalarmin or its analogs might represent a novel class of non-steroidal inhibitors of pregnancy at its very early stages. Furthermore, CRH was shown to inhibit interstitial trophoblast invasion in vitro, by decreasing the expression of CEACAM1 on extravillous trophoblasts. This effect was mediated by CRH-R1, since the addition of antalarmin completely reversed it. It was, therefore, suggested that a defective CRH/CRH-R1 system might be involved in the pathophysiology of clinical conditions characterized by impaired trophoblast invasion, such as preeclampsia and placenta accreta (71). Given the promising future of CRH antagonists in the therapy of depression and anxiety disorders, their effects on reproductive physiology should be thoroughly examined.

In humans, placental CRH is secreted mostly during the latter half of pregnancy and is responsible for the physiologic hypercortisolism observed during this period (72). Placental CRH expression increases during the last week of pregnancy. Placental CRH drives the pituitary–adrenal axis to produce increased amounts of cortisol during the latter half of pregnancy. CRH may be the placental clock determining the onset of parturition (73). Interestingly, maternal CRH levels are significantly elevated in the plasma of women with preterm labor (74). This is further supported by findings showing that CRH infused into preterm fetal sheep precipitated early parturition (75). CRH-R1 antagonism in the late gestation of fetal sheep, using antalarmin, delays the onset of parturition. Finally, in rats, administration of antalarmin after the fifth day of gestation and until the end of pregnancy has no abortifacient or fetotoxic effect, suggesting that CRH antagonists could be used to protect the fetus from maternal stress and/or to prevent premature labor and delivery (70).

GI diseases with high incidence, such as functional bowel disorders, irritable bowel syndrome (IBS), and peptic ulcer are related to stressful stimuli. Acute stressors inhibit gastric motility and emptying, whereas they exert stimulating effects in the lower GI tract, manifested by increased colonic motility, decreased colonic transit time, defecation, and watery diarrhea. CRH-R1 seems to be the major receptor type mediating the colonic stress-related phenomena. Indeed, CRH-induced colonic effects were reversed by non-selective CRH-R1/CRH-R2 peptidic antagonists and not by selective peptidic CRH-R2 antagonists (76–78). Moreover, the specific CRH-R2 ligands Ucn 2 and Ucn 3 had no effect on colonic function (77, 79, 80). Both central and peripheral pathways seem to contribute to these effects (81, 82). Interestingly, non-peptidic selective CRH-R1 receptor antagonists, such as CP-154,526, CRA-1000, NBI-35 965, NBI-27 914, and antalarmin, injected peripherally, i.c.v., or given orally, blunted the colonic-stimulating effects induced by restraint or social stress, water avoidance or morphine withdrawal (83–89). These results, combined with in vivo data that confirm that selective non-peptidic CRH-R1 antagonists can inhibit stress or CRH-induced hyperalgesia to colorectal distention (90, 91), suggest a therapeutic potential of such compounds in IBS. Given the pro-inflammatory actions mediated by CRH receptors, CRH antagonists could benefit patients with ulcerative colitis, a common disorder characterized by chronic inflammation of the bowel that is related to increased levels of CRH and Ucn 2.

CRH-R2 seems to be the major receptor type mediating stress and CRH-related gastric motor alterations, however, antalarmin can inhibit stress-induced gastric ulcerogenesis in rats, possibly by blockade of brain CRH-R1 and vagal pathways (52). A prophylactic potential of CRH-R1 antagonists against ulcer is anticipated.

Conditions such as chronic stress-induced metabolic syndrome and congenital adrenal hyperplasia, associated with elevations of CRH secretion, might benefit from therapy with CRH antagonists. Also, pituitary ACTH-secreting adenomas that are dependent upon CRH stimulation might be controlled by CRH antagonists.

CRH-related peptides acting on CRH-R2 could, in theory, reduce stress-induced suppression of appetite, stimulate hypothalamic CRH secretion by interrupting putative CRH-R2-mediated auto-inhibition of CRH, and block CRH-R2-mediated peripheral vasodilatation (92–94). However, the potent cardiac inotropic actions of Ucn in rodents and sheep, its coronary vasodilatory actions in sheep, cardioprotective properties in mice and rats, and antivascularization effects in mice, suggest that any clinical experimentation with antagonists for CRH-R2 should be done cautiously. Such antagonists might be useful in the treatment of cancer- or AIDS-related anorexia and cachexia, atypical depression, chronic pain and fatigue syndromes, syndromes of excessive daytime sleepiness and cytokine-induced hypotension (95–98).

Footnotes

This paper was presented at the 4th Ferring Pharmaceuticals International Paediatric Endocrinology Symposium, Paris (2006). Ferring Pharmaceuticals has supported the publication of these proceedings.

References

    1. Vale W, Spiess J, Rivier C & Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981 213 1394–1397.[Free Full Text]

    2. Brown MR, Rivier C & Vale W. Central nervous system regulation of adrenocorticotropin secretion: role of somatostatins. Endocrinology 1984 114 1546–1549.[Abstract]

    3. Jingami H, Mizuno N, Takahashi H, Shibahara S, Furutani Y, Imura H & Numa S. Cloning and sequence analysis of cDNA for rat corticotropin-releasing factor precursor. FEBS Letters 1985 191 63–66.[CrossRef][ISI][Medline]

    4. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D & Rivier C. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995 378 287–292.[CrossRef][Medline]

    5. Spina M, Merlo-Pich E, Chan RK, Basso AM, Rivier J, Vale W & Koob GF. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 1996 273 1561–1564.[Abstract]

    6. Hsu SY & Hsueh AJ. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nature Medicine 2001 7 605–611.[CrossRef][ISI][Medline]

    7. Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE & Vale WW. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. PNAS 2001 98 7570–7575.[Abstract/Free Full Text]

    8. Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW & Sawchenko PE. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. PNAS 2001 98 2843–2848.[Abstract/Free Full Text]

    9. Turnbull AV, Vale W & Rivier C. Urocortin, a corticotropin-releasing factor-related mammalian peptide, inhibits edema due to thermal injury in rats. European Journal of Pharmacology 1996 303 213–216.[CrossRef][ISI][Medline]

    10. Parkes DG, Vaughan J, Rivier J, Vale W & May CN. Cardiac inotropic actions of urocortin in conscious sheep. American Journal of Physiology 1997 272 H2115–H2122.[ISI][Medline]

    11. Li C, Chen P, Vaughan J, Blount A, Chen A, Jamieson PM, Rivier J, Smith MS & Vale W. Urocortin III is expressed in pancreatic beta-cells and stimulates insulin and glucagon secretion. Endocrinology 2003 144 3216–3224.[Abstract/Free Full Text]

    12. Eckart K, Jahn O, Radulovic J, Tezval H, van Werven L & Spiess J. A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists. PNAS 2001 98 11142–11147.[Abstract/Free Full Text]

    13. Bale TL, Giordano FJ, Hickey RP, Huang Y, Nath AK, Peterson KL, Vale WW & Lee KF. Corticotropin-releasing factor receptor 2 is a tonic suppressor of vascularization. PNAS 2002 99 7734–7739.[Abstract/Free Full Text]

    14. Chen R, Lewis KA, Perrin MH & Vale WW. Expression cloning of a human corticotropin-releasing-factor receptor. PNAS 1993 90 8967–8971.[Abstract/Free Full Text]

    15. Ross PC, Kostas CM & Ramabhadran TV. A variant of the human corticotropin-releasing factor (CRF) receptor: cloning, expression and pharmacology. Biochemical and Biophysical Research Communications 1994 205 1836–1842.[CrossRef][ISI][Medline]

    16. Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ & Hillhouse EW. A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes. Molecular Endocrinology 1999 13 2189–2202.[Abstract/Free Full Text]

    17. Pisarchik A & Slominski AT. Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression. Federation of American Societies for Experimental Biology 2001 15 2754–2756.

    18. Liaw CW, Lovenberg TW, Barry G, Oltersdorf T, Grigoriadis DE & de Souza EB. Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 1996 137 72–77.[Abstract]

    19. Valdenaire O, Giller T, Breu V, Gottowik J & Kilpatrick G. A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor. Biochimica et Biophysica Acta 1997 1352 129–132.[Medline]

    20. Kostich WA, Chen A, Sperle K & Largent BL. Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2{gamma} receptor. Molecular Endocrinology 1998 12 1077–1085.[Abstract/Free Full Text]

    21. Lovenberg TW, Chalmers DT, Liu C & De Souza EB. CRF2{alpha} and CRF2ß receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 1995 136 4139–4142.[Abstract]

    22. Rivier J, Rivier C & Vale W. Synthetic competitive antagonists of corticotropin-releasing factor: effect on ACTH secretion in the rat. Science 1984 224 889–891.[Abstract/Free Full Text]

    23. Barquist E, Zinner M, Rivier J & Tache Y. Abdominal surgery-induced delayed gastric emptying in rats: role of CRF and sensory neurons. American Journal of Physiology 1992 262 G616–G620.[Medline]

    24. Nozu T, Martinez V, Rivier J & Tache Y. Peripheral urocortin delays gastric emptying: role of CRF receptor 2. American Journal of Physiology 1999 276 G867–G874.[Medline]

    25. Gilligan PJ & Li YW. Corticotropin-releasing factor antagonists: recent advances and exciting prospects for the treatment of human diseases. Current Opinion in Drug Discovery and Development 2004 7 487–497.

    26. Zorrilla EP & Koob GF. The therapeutic potential of CRF1 antagonists for anxiety. Expert Opinion on Investigational Drugs 2004 13 799–828.[CrossRef][ISI][Medline]

    27. Arvanitis AG, Gilligan PJ, Chorvat RJ, Cheeseman RS, Christos TE, Bakthavatchalam R, Beck JP, Cocuzza AJ, Hobbs FW, Wilde RG, Arnold C, Chidester D, Curry M, He L, Hollis A, Klaczkiewicz J, Krenitsky PJ, Rescinito JP, Scholfield E, Culp S, De Souza EB, Fitzgerald L, Grigoriadis D, Tam SW & Shen HL. Non-peptide corticotropin-releasing hormone antagonists: syntheses and structure-activity relationships of 2-anilinopyrimidines and -triazines. Journal of Medicinal Chemistry 1999 42 805–818.[CrossRef][ISI][Medline]

    28. Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Nakazato A, Kumagai T, Okubo T & Tomisawa K. Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001. Journal of Pharmacology and Experimental Therapeutics 1999 289 926–935.[Abstract/Free Full Text]

    29. Griebel G, Perrault G & Sanger DJ. Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents. Comparison with diazepam and buspirone. Psychopharmacology (Berl) 1998 138 55–66.[CrossRef][Medline]

    30. Piekut DT & Phipps B. Corticotropin-releasing factor – immuno-labeled fibers in brain regions with localized kainate neurotoxicity. Acta Neuropathologica (Berl) 1999 98 622–628.

    31. Mackay KB, Bozigian H, Grigoriadis DE, Loddick SA, Verge G & Foster AC. Neuroprotective effects of the CRF1 antagonist R121920 after permanent focal ischemia in the rat. Journal of Cerebral Blood Flow and Metabolism 2001 21 1208–1214.[ISI][Medline]

    32. Baram TZ, Chalmers DT, Chen C, Koutsoukos Y & De Souza EB. The CRF1 receptor mediates the excitatory actions of corticotropin-releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist. Brain Research 1997 770 89–95.[CrossRef][ISI][Medline]

    33. Theoharides TC, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, Rozniecki JJ, Webster E & Chrousos GP. Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect. Endocrinology 1995 136 5745–5750.[Abstract]

    34. Sarnyai Z, Shaham Y & Heinrichs SC. The role of corticotropin-releasing factor in drug addiction. Pharmacological Reviews 2001 53 209–243.[Abstract/Free Full Text]

    35. Shaham Y, Erb S, Leung S, Buczek Y & Stewart J. CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats. Psychopharmacology (Berl) 1998 137 184–190.[CrossRef][Medline]

    36. Stinus L, Cador M, Zorrilla EP & Koob GF. Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology 2005 30 90–98.[CrossRef][ISI][Medline]

    37. Valdez GR & Koob GF. Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism. Pharmacology Biochemistry and Behavior 2004 79 671–689.[CrossRef][ISI][Medline]

    38. Goeders NE & Clampitt DM. Potential role for the hypothalamo–pituitary–adrenal axis in the conditioned reinforcer-induced reinstatement of extinguished cocaine seeking in rats. Psychopharmacology (Berl) 2002 161 222–232.[Medline]

    39. Przegalinski E, Filip M, Frankowska M, Zaniewska M & Papla I. Effects of CP-154,526, a CRF1 receptor antagonist, on behavioral responses to cocaine in rats. Neuropeptides 2005 39 525–533.[CrossRef][ISI][Medline]

    40. Gravanis A & Margioris AN. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Current Medicinal Chemistry 2005 12 1503–1512.[CrossRef][ISI][Medline]

    41. Berkenbosch F, van Oers J, del Rey A, Tilders F & Besedovsky H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 1987 238 524–526.[Abstract/Free Full Text]

    42. Sapolsky R, Rivier C, Yamamoto G, Plotsky P & Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987 238 522–524.[Abstract/Free Full Text]

    43. Lumpkin MD. The regulation of ACTH secretion by IL-1. Science 1987 238 452–454.[Free Full Text]

    44. Chrousos GP. The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. New England Journal of Medicine 1995 332 1351–1362.[Free Full Text]

    45. Karalis K, Sano H, Redwine J, Listwak S, Wilder RL & Chrousos GP. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science 1991 254 421–423.[Abstract/Free Full Text]

    46. Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC & Chrousos GP. In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 1996 137 5747–5750.[Abstract]

    47. Radulovic M, Dautzenberg FM, Sydow S, Radulovic J & Spiess J. Corticotropin-releasing factor receptor 1 in mouse spleen: expression after immune stimulation and identification of receptor-bearing cells. Journal of Immunology 1999 162 3013–3021.[Abstract/Free Full Text]

    48. Venihaki M, Zhao J & Karalis KP. Corticotropin-releasing hormone deficiency results in impaired splenocyte response to lipopolysaccharide. Journal of Neuroimmunology 2003 141 3–9.[CrossRef][ISI][Medline]

    49. Venihaki M, Dikkes P, Carrigan A & Karalis KP. Corticotropin-releasing hormone regulates IL-6 expression during inflammation. Journal of Clinical Investigation 2001 108 1159–1166.[CrossRef][ISI][Medline]

    50. Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S, Gabry KE, Chrousos GP, McCarthy EF, Rice KC, Gold PW & Sternberg EM. Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation. Journal of Rheumatology 2002 29 1252–1261.[ISI][Medline]

    51. Agelaki S, Tsatsanis C, Gravanis A & Margioris AN. Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice. Infection and Immunity 2002 70 6068–6074.[Abstract/Free Full Text]

    52. Gabry KE, Chrousos GP, Rice KC, Mostafa RM, Sternberg E, Negrao AB, Webster EL, McCann SM & Gold PW. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. Molecular Psychiatry 2002 7 474–483.[CrossRef][ISI][Medline]

    53. Uzuki M, Sasano H, Muramatsu Y, Totsune K, Takahashi K, Oki Y, Iino K & Sawai T. Urocortin in the synovial tissue of patients with rheumatoid arthritis. Clinical Science (London) 2001 100 577–589.

    54. Crofford LJ, Sano H, Karalis K, Friedman TC, Epps HR, Remmers EF, Mathern P, Chrousos GP & Wilder RL. Corticotropin-releasing hormone in synovial fluids and tissues of patients with rheumatoid arthritis and osteoarthritis. Journal of Immunology 1993 151 1587–1596.[Abstract]

    55. Kohno M, Kawahito Y, Tsubouchi Y, Hashiramoto A, Yamada R, Inoue KI, Kusaka Y, Kubo T, Elenkov IJ, Chrousos GP, Kondo M & Sano H. Journal of Clinical Endocrinology and Metabolism 2001 86 4344–4352.[Abstract/Free Full Text]

    56. Kawahito Y, Sano H, Mukai S, Asai K, Kimura S, Yamamura Y, Kato H, Chrousos GP, Wilder RL & Kondo M. Urocortin expression in synovium of patients with rheumatoid arthritis and osteoarthritis: relation to inflammatory activity. Gut 1995 37 544–551.[Abstract/Free Full Text]

    57. Saruta M, Takahashi K, Suzuki T, Torii A, Kawakami M & Sasano H. Journal of Clinical Endocrinology and Metabolism 2004 89 5352–5361.[Abstract/Free Full Text]

    58. Chatzaki E, Charalampopoulos I, Leontidis C, Mouzas IA, Tzardi M, Tsatsanis C, Margioris AN & Gravanis A. Urocortin in human gastric mucosa: relationship to inflammatory activity. Journal of Clinical Endocrinology and Metabolism 2003 88 478–483.[Abstract/Free Full Text]

    59. Kempuraj D, Papadopoulou N, Stanford EJ, Christodoulou S, Madhappan B, Sant GR, Solage K, Adams T & Theoharides TC. Increased numbers of activated mast cells in endometriosis lesions positive for corticotropin-releasing hormone and urocortin. American Journal of Reproductive Immunology 2004 52 267–275.[CrossRef]

    60. Scopa CD, Mastorakos G, Friedman TC, Melachrinou M, Merino MJ & Chrousos GP. Presence of immunoreactive corticotropin releasing hormone in thyroid lesions. American Journal of Pathology 1994 145 1159–1167.[Abstract]

    61. Benou C, Wang Y, Imitola J, VanVlerken L, Chandras C, Karalis KP & Khoury SJ. Corticotropin-releasing hormone contributes to the peripheral inflammatory response in experimental autoimmune encephalomyelitis. Journal of Immunology 2005 174 5407–5413.[Abstract/Free Full Text]

    62. Theoharides TC, Donelan JM, Papadopoulou N, Cao J, Kempuraj D & Conti P. Mast cells as targets of corticotropin-releasing factor and related peptides. Trends in Pharmacological Sciences 2004 25 563–568.[CrossRef][Medline]

    63. Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E & Chrousos G. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology 1998 139 403–413.[Abstract/Free Full Text]

    64. Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL & Theoharides TC. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. Journal of Immunology 2005 174 7665–7675.[Abstract/Free Full Text]

    65. Chrousos GP, Torpy DJ & Gold PW. Interactions between the hypothalamic–pituitary–adrenal axis and the female reproductive system: clinical implications. Annals of Internal Medicine 1998 129 229–240.[Abstract/Free Full Text]

    66. Kalantaridou SN, Makrigiannakis A, Zoumakis E & Chrousos GP. Stress and the female reproductive system. Journal of Reproductive Immunology 2004 62 61–68.[CrossRef][ISI][Medline]

    67. Kalantaridou SN, Makrigiannakis A, Zoumakis E & Chrousos GP. Reproductive functions of corticotropin-releasing hormone. Research and potential clinical utility of antalarmins (CRH receptor type 1 antagonists). American Journal of Reproductive Immunology 2004 51 269–274.

    68. Makrigiannakis A, Margioris AN, Le Goascogne C, Zoumakis E, Nikas G, Stournaras C, Psychoyos A & Gravanis A. Corticotropin-releasing hormone (CRH) is expressed at the implantation sites of early pregnant rat uterus. Life Sciences 1995 57 1869–1875.[CrossRef][ISI][Medline]

    69. Zoumakis E, Margioris AN, Stournaras C, Dermitzaki E, Angelakis E, Makrigiannakis A, Koumantakis E & Gravanis A. Corticotrophin-releasing hormone (CRH) interacts with inflammatory prostaglandins and interleukins and affects the decidualization of human endometrial stroma. Molecular Human Reproduction 2000 6 344–351.[Abstract/Free Full Text]

    70. Makrigiannakis A, Zoumakis E, Kalantaridou S, Coutifaris C, Margioris AN, Coukos G, Rice KC, Gravanis A & Chrousos GP. Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance. Nature Immunology 2001 2 1018–1024.[CrossRef][ISI][Medline]

    71. Bamberger AM, Minas V, Kalantaridou SN, Radde J, Sadeghian H, Loning T, Charalampopoulos I, Brummer J, Wagener C, Bamberger CM, Schulte HM, Chrousos GP & Makrigiannakis A. Corticotropin-releasing hormone modulates human trophoblast invasion through carcinoembryonic antigen-related cell adhesion molecule-1 regulation. American Journal of Pathology 2006 168 141–150.[Abstract/Free Full Text]

    72. Neulen J & Breckwoldt M. Placental progesterone, prostaglandins and mechanisms leading to initiation of parturition in the human. Experimental and Clinical Endocrinology 1994 102 195–202.[ISI][Medline]

    73. McLean M, Bisits A, Davies J, Woods R, Lowry P & Smith R. A placental clock controlling the length of human pregnancy. Nature Medicine 1995 1 460–463.[CrossRef][ISI][Medline]

    74. Challis JR. CRH, a placental clock and preterm labour. Nature Medicine 1995 1 416.[CrossRef][ISI][Medline]

    75. Chan EC, Falconer J, Madsen G, Rice KC, Webster EL, Chrousos GP & Smith RA. Corticotropin-releasing hormone type I receptor antagonist delays parturition in sheep. Endocrinology 1998 139 3357–3360.[Abstract/Free Full Text]

    76. Tache Y, Martinez V, Million M & Wang L. Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. American Journal of Physiology. Gastrointestinal and Liver Physiology 2001 280 G173–G177.[Abstract/Free Full Text]

    77. Martinez V, Wang L, Rivier JE, Vale W & Tache Y. Differential actions of peripheral corticotropin-releasing factor (CRF), urocortin II, and urocortin III on gastric emptying and colonic transit in mice: role of CRF receptor subtypes 1 and 2. Journal of Pharmacology and Experimental Therapeutics 2002 301 611–617.[Abstract/Free Full Text]

    78. Million M, Maillot C, Saunders P, Rivier J, Vale W & Tache Y. Human urocortin II, a new CRF-related peptide, displays selective CRF(2)-mediated action on gastric transit in rats. American Journal of Physiology. Gastrointestinal and Liver Physiology 2002 282 G34–G40.[Abstract/Free Full Text]

    79. Miampamba M, Germano PM, Arli S, Wong HH, Scott D, Tache Y & Pisegna JR. Expression of pituitary adenylate cyclase-activating polypeptide and PACAP type 1 receptor in the rat gastric and colonic myenteric neurons. Regulatory Peptides 2002 105 145–154.[ISI][Medline]

    80. Saunders PR, Maillot C, Million M & Tache Y. Peripheral corticotropin-releasing factor induces diarrhea in rats: role of CRF1 receptor in fecal watery excretion. European Journal of Pharmacology 2002 435 231–235.[CrossRef][ISI][Medline]

    81. Muramatsu Y, Fukushima K, Iino K, Totsune K, Takahashi K, Suzuki T, Hirasawa G, Takeyama J, Ito M, Nose M, Tashiro A, Hongo M, Oki Y, Nagura H & Sasano H. Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa. Peptides 2000 21 799–1809.

    82. Chatzaki E, Crowe PD, Wang L, Million M, Tache Y & Grigoriadis DE. CRF receptor type 1 and 2 expression and anatomical distribution in the rat colon. Journal of Neurochemistry 2004 90 309–316.[CrossRef][ISI][Medline]

    83. 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. 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 2000 97 6079–6084.[Abstract/Free Full Text]

    84. Lu L, Liu D, Ceng X & Ma L. Differential roles of corticotropin-releasing factor receptor subtypes 1 and 2 in opiate withdrawal and in relapse to opiate dependence. European Journal of Neuroscience 2000 12 4398–4404.[CrossRef][ISI][Medline]

    85. Maillot C, Million M, Wei JY, Gauthier A & Tache Y. Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology 2000 119 1569–1579.[CrossRef][ISI][Medline]

    86. Funada M, Hara C & Wada K. Involvement of corticotropin-releasing factor receptor subtype 1 in morphine withdrawal regulation of the brain noradrenergic system. European Journal of Pharmacology 2001 430 277–281.[CrossRef][ISI][Medline]

    87. Martinez V & Tache Y. Role of CRF receptor 1 in central CRF-induced stimulation of colonic propulsion in rats. Brain Research 2001 893 29–35.[CrossRef][ISI][Medline]

    88. Bale TL, Picetti R, Contarino A, Koob GF, Vale WW & Lee KF. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. Journal of Neuroscience 2002 22 193–199.[Abstract/Free Full Text]

    89. Martinez V, Wang L, Rivier J, Grigoriadis D & Tache Y. Central CRF, urocortins and stress increase colonic transit via CRF1 receptors while activation of CRF2 receptors delays gastric transit in mice. Journal of Physiology 2004 556 221–234.[Abstract/Free Full Text]

    90. Gue M, Del Rio-Lacheze C, Eutamene H, Theodorou V, Fioramonti J & Bueno L. Stress-induced visceral hypersensitivity to rectal distension in rats: role of CRF and mast cells. Neurogastroenterology and Motility 1997 9 271–279.[CrossRef][ISI][Medline]

    91. Greenwood-Van Meerveld B, Johnson AC, Foreman RD & Linderoth B. Spinal cord stimulation attenuates visceromotor reflexes in a rat model of post-inflammatory colonic hypersensitivity. Autonomic Neuroscience 2005 122 69–76.[CrossRef][ISI][Medline]

    92. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D & Rivier C. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995 378 287–292.[CrossRef][Medline]

    93. Hsu SY & Hsueh AJW. Human stesscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nature Medicine 2001 7 605–611.[CrossRef][ISI][Medline]

    94. Pelleymounter MA, Joppa M, Carmouche M, Cullen MJ, Brown B, Murphy B, Grigoriadis DE, Ling N & Foster AC. Role of corticotropin-releasing factor (CRF) receptors inthe anorexic syndrome induced by CRF. Journal of Pharmacology and Experimental Therapeutics 2002 293 799–806.

    95. Vetter DE, Li C, Zhao L, Contarino A, Liberman MC, Smith GW, Marchuk Y, Koob GF, Heinemann SF, Vale W & Lee KF. Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior. Nature Genetics 2002 31 363–369.[CrossRef][ISI][Medline]

    96. Parkes GD & May CN. Urocortin: a novel player in cardiac control. News in Physiological Sciences 2000 15 264–268.[Abstract/Free Full Text]

    97. Gold PW & Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high versus low CRH/NE States. Molecular Psychiatry 2002 7 254–275.[CrossRef][ISI][Medline]

    98. Vgontzas AN, Vela-Bueno A & Chrousos GP. Endocrine disorders and sleep. In Sleep Medicine, pp 477–487. Ed. TL Lee-Chiong, Philadelphia, PA: Hanley & Belfus, 2002.

Received 11 July 2006
Accepted 17 July 2006





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zoumakis, E
Right arrow Articles by Chrousos, G P
Right arrow Search for Related Content
PubMed
Right arrow Articles by Zoumakis, E
Right arrow Articles by Chrousos, G P

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS