OBJECTIVE:To determine whether a corticotropin releasing hormone (CRH) type 1-specific receptor antagonist, antalarmin, would alter the progression of inflammation in adjuvant induced arthritis (AIA) susceptible LEW/N rats by blocking local CRH mediated inflammatory responses or render AIA resistant F344/N rats more susceptible to AIA by blocking central CRH, thus reducing secretion of endogenous glucocorticoids.METHODS:F344/N and LEW/N rats were assigned to either drug or vehicle groups and treated with 20 mg/kg antalarmin or vehicle alone BID for 25 days by intraperitoneal injection. Arthritis was induced in both antalarmin and vehicle treated LEW/N and F344/N rats by subcutaneous injections at the base of the tail of incomplete Freund's adjuvant containing 10 mg/ml heat killed Mycobacterium tuberculosis. Control F344/N and LEW/N rats were maintained on either antalarmin or vehicle.RESULTS:Chronic blockade of CRH-R1 with systemic antalarmin significantly ameliorated AIA in LEW/N rats, reducing the severity of inflammation in peripheral joints, evidenced by clinical and histopathology scores, and weight loss associated with disease onset. Antalarmin neither induced nor exacerbated arthritis expression in F344/N or LEW/N rats, despite suppression of levels of adjuvant induced corticosterone, the major antiinflammatory glucocorticoid in rats.CONCLUSION:Systemic blockade of CRH-RI appeared to predominantly block peripheral proinflammatory effects of immune CRH, rather than the systemic glucocorticoid mediated antiinflammatory effects of hypothalamic CRH. Results indicate that chronic treatment with a CRH antagonist attenuates progressive inflammation induced degeneration of synovia, cartilage, and bone in arthritic joints, suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders.

Antalarmin (butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine) was doubly labelled with carbon-13. The synthesized butyl-[C-13(2)]ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (1) and butyl-ethyl-[2-C-13] -[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]-[2-C-13] pyrimidin-4-yl]amine, (2) were prepared for use as substrates for pharmacokinetic studies. These compounds were obtained in fair overall yield in a 5 and 6 step synthesis (20-24.5%, respectively) and high isotopic purity (about 99 at% C-13). Copyright (C) 2002 John Wiley Sons, Ltd.

When exposed to prolonged stress, rats develop gastric ulceration, enhanced colon motility with depletion of its mucin content and signs of physiological and behavioral arousal. In this model, we tested whether antidepressants (fluoxetine and bupropion), anxiolytics (diazepam and buspirone) or the novel nonpeptide corticotropin-releasing hormone (CRH) type-1 receptor (CRH-R1) antagonist, antalarmin, modify these responses. Fluoxetine, bupropion, diazepam and antalarmin all suppressed stress-induced gastric ulceration in male Sprague–Dawley rats exposed to four hours of plain immobilization. Antalarmin produced the most pronounced anti-ulcer effect and additionally suppressed the stress-induced colonic hypermotility, mucin depletion, autonomic hyperarousal and struggling behavior. Intraperitoneal CRH administration reproduced the intestinal but not the gastric responses to stress while vagotomy antagonized the stress-induced gastric ulceration but not the intestinal responses. We conclude that brain CRH-R1 and vagal pathways are essential for gastric ulceration to occur in response to stress and that peripheral CRH-R1 mediates colonic hypermotility and mucin depletion in this model. Nonpeptide CRH-R1 antagonists may therefore be prophylactic against stress ulcer in the critically ill and therapeutic for other pathogenetically related gastrointestinal disorders such as peptic ulcer disease and irritable bowel syndrome.

A series of compounds related to N-butyl-N-ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (1, antalarmin) have been prepared and evaluated for their CRHR1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (delta-hydroxy or bis-beta-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor. Introducing an amino group or shortening the alkyl side chain was detrimental to CRHR1 affinity. The alcohol 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]butan-1-ol (3), bearing a terminal hydroxyl group on an N-alkyl side-chain, showed the highest CRHR1 binding affinity among these compounds (K(i)=0.68 nM), and is one of the highest affinity CRHR1 ligands known. Compounds 3-5, and 8, which are likely to be less lipophilic than 1, have high CRHR1 affinity and may be valuable probes to further study the CRH system.

A high-affinity radioligand for CRHR1 has been prepared that can serve as a template for the development of SPECT imaging agents. The 5-chloro-N-cyclopropylmethyl-N-(2,6-dichloro-4-iodophenyl)-2-methyl-N-propylpyrimidine-4,6-diamine (6b, Ki=14 nM), and the corresponding 4-bromophenyl analogue (6a, Ki=21 nM), were synthesized in four steps from compound 3.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

A series of fluoro-substituted 4-(dialkylamino)pyrrolo[2,3-d]pyrimidines was synthesized and their binding affinity for corticotropin-releasing hormone type 1 receptor (CRHR1) was investigated. Compounds 11a and 11b possessed very high CRHR1 affinity (Ki=3.5, 0.91 nM, respectively). They are promising candidates for the development of 18F-containing nonpeptide PET radioligands for CRHR1.

[H-3](4-Fluorobutyl)propyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine ([H-3]LWH-154), a novel potent radiolabelled analog of the nonpeptide corticotropin-releasing hormone type I receptor (CRHR1) selective antagonist, butylethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (antalarmin), was prepared for the development of positron emission tomography radiotracers for CRHR1 and evaluation as a nonpeptide radioligand for use in pharmacological studies. The precursor (4-fluorobutyl)prop-2-enyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (6) for tritiation was prepared in two steps from 3 in 76% total yield. Catalytic reduction of unsaturated fluoride 6 using tritium gas and palladium as catalyst gave [H-3]LWH-154. After HPLC purification, [H-3]LWH-154 of high radiochemical purity was obtained with a specific activity of 69 Ci/mmol.

Antalarmin is a pyrrolopyrimidine compound that antagonizes corticotropin-releasing hormone (CRH) type 1 receptors (CRHR1). In order to assess the effects of antalarmin treatment on hypothalamic-pituitary-adrenal (HPA) function we measured the plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in animals treated with either antalarmin or vehicle for 1 week or for 8 weeks. We found that antalarmin treatment for 1 week did not affect basal concentrations of ACTH or corticosterone. In contrast, treatment for 8 weeks significantly lowered basal ACTH and corticosterone concentrations and also significantly decreased the basal corticosterone to ACTH ratio, indicating decreased basal adrenocortical responsiveness to ACTH. However, immobilization stress resulted in ACTH and corticosterone concentrations that were the same in animals treated with vehicle or antalarmin for either 1 or 8 weeks. We conclude that even though 8-week antagonism of CRHR1 by the non-peptide antalarmin blunts basal concentrations of ACTH and corticosterone, and affects the adrenal responsiveness to ACTH, it does not blunt the HPA response to acute stress, and it does not appear to cause stress-induced adrenal insufficiency.

Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous inflammation model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of urocortin- and hydralazine-induced hypotension on acute inflammation induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and urocortin (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 ± 0.5 ml (controls) to 2.4 ± 0.3 ml (p = 0.004) and 2.9 ± 0.6 ml (p = 0.007) in urocortin- and hydralazine-treated animals, respectively. Urocortin and hydralazine both produced a significant fall in blood pressure compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 ± 4.1 (p < 0.001) and 34.6 ± 4.6 (p < 0.001) vs. 92.9 ± 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0.52, p = 0.007). As both hydralazine and urocortin lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of urocortin and related neuropeptides may be nonspecific, acting through hypotension rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension.

A bstract : Corticotropin‐releasing hormone (CRH) influences the immune system indirectly, through activation of the hypothalamic‐pituitary‐adrenal axis and sympathetic system, and directly, through local modulatory actions of peripheral (immune) CRH. We recently demonstrated that catecholamines and histamine potently inhibited interleukin (IL)‐12 and stimulated IL‐10, whereas glucocorticoids suppressed IL‐12, but did not affect IL‐10 production ex vivo . Thus, both glucocorticoids and catecholamines, the end products of the stress system, and histamine, a product of activated mast cells, may selectively suppress cellular immunity and favor humoral immune responses. We localized immunoreactive CRH in experimental carrageenin‐induced aseptic inflammation and, in humans, in inflamed tissues from patients with several autoimmune diseases. In addition, we demonstrated that CRH activated mast cells via a CRH receptor type 1‐dependent mechanism, leading to release of histamine and hence vasodilatation and increased vascular permeability. Thus, activation of the stress system, through direct and indirect effects of CRH, may influence the susceptibility of an individual to certain autoimmune, allergic, infectious or neoplastic diseases. Antalarmin, a novel nonpeptide CRH antagonist, prevented several proinflammatory effects of CRH, thus revealing its therapeutic potential in some forms of inflammation.

CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound, antagonizes CRH type 1 receptor-mediated effects of CRH, including pituitary ACTH release, stress behaviors, and acute inflammation. We administered antalarmin chronically to evaluate its effects on hypothalamic-pituitary-adrenal axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of i.p. antalarmin or placebo over 11 days. The animals were weighed; plasma ACTH, corticosterone, leptin, and blood glucose levels were determined; and morphometric analyses were performed to determine adrenal size and structure, including sizing, histochemistry, immunohistochemistry, and electron microscopy. Leptin messenger RNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH (mean +/- SD, 2.62 +/- 0.063 pg/ml) and corticosterone concentrations (10.21 +/- 1.80 microg/dl) compared with those in vehicle-treated rats [respectively, 5.3 +/- 2.0 (P < 0.05) and 57.02 +/- 8.86 (P < 0.01)]. Antalarmin had no significant effect on body weight, plasma leptin, or blood glucose concentrations or fat cell leptin messenger RNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced by 31% compared with that in controls without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. The apoptotic rate was increased in the outer zona fasciculata of animals treated with the antagonist (26.6 +/- 3.58%) compared with that in placebo-treated controls (6.8 +/- 0.91%). We conclude that chronic administration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, whereas it reduces adrenocortical function mildly, without anatomical, clinical, or biochemical evidence of causing adrenal atrophy. These results are promising for future uses of such an antagonist in the clinic.

In sheep, corticotropin-releasing hormone (CRH) can stimulate the fetal release of ACTH to produce a cortisol surge which leads to the onset of parturition. We tested the hypothesis that fetal CRH is a primary factor in the onset of parturition in sheep by using a Type I CRH receptor antagonist, antalarmin, to block the endogenous action of CRH. Pregnant ewes were cannulated at 130-135 days of gestation. Five catheters were placed into the amniotic sac, fetal femoral artery, fetal tarsal vein, maternal jugular vein and carotid artery. After 5 days' recovery, blood samples from maternal and fetal vessels were collected at the following times: a day before the start of infusion, at [-1, 0, 1, 2, 4, 8 and 24]h, on the first day of infusion, and thereafter daily throughout a 10-day infusion. Animals (n=6 per group) received infusions into a fetal vein of either a vehicle comprising 1:1 mixture of ethanol and polyethoxylated castor oil (Cremophor EL) or antalarmin (50 g/L) in the vehicle at a rate of 0.3 mL/h. The plasma samples were assayed for ACTH and cortisol using commercial RIA kits. Fetuses infused with vehicle delivered at a mean gestational age of 141.8 +/- 0.9 days compared with antalarmin-infused sheep at 148.8 +/- 1.6 days (P = 0.0036, unpaired Student's t-test). Fetal ACTH and cortisol did not change in the antalarmin-infused sheep after 3 days' infusion compared to significant increases in vehicle-infused sheep (P=0.004 and P = 0.016 respectively, ANOVA). These data show that CRH receptor antagonism in the fetus can delay the onset of parturition. It supports the hypothesis that hypothalamic CRH drives fetal production of ACTH and is essential for the onset of parturition triggered by a surge in fetal cortisol.

Abstract: Cortic otropin‐releasing hormone (CRH) is a major regulator of the hypothalamic‐pituitary‐adrenal axis (HPA) and principal coordinator of the stress response. As in stress, intracerebroventricular administration of CRH suppresses the immune system indirectly, via glucocorticoid and/or sympathetic system‐mediated mechanisms. Also, during inflammatory stress, the cytokines TNFα, IL‐1, and IL‐6 stimulate hypothalamic CRH and/or vasopressin secretion as a way of preventing the inflammatory reaction from overreacting. Recently, CRH receptors were described in peripheral sites of the immune system, and CRH was found to promote several immune functions in vitro. We demonstrated a direct role of CRH in the inflammatory immune process in vivo, by first studying the effect of systemic CRH immunoneutralization in an experimental model of carrageenin‐induced aseptic inflammation in Spague‐Dawley rats. We extended these observations to other forms of experimental inflammation, including streptococcal cell wall polysaccharide‐ and adjuvant‐induced arthritides and peptide R16 (epitope of the interphotoreceptor retinoid‐binding protein)‐induced uveitis in Lewis rats. We also studied human disease states, including rheumatoid arthritis, Hashimoto thyroiditis, and ulcerative colitis. Inflamed tissues contained large amounts of IR CRH, reaching levels similar to those observed in the hypophyseal portal system. We also demonstrated the presence of CRH mRNA and CRH receptors in inflammatory cells and identified the mast cells as a major immune target for CRH. In addition to production by immune cells, the peripheral nervous system, including the postganglionic sympathetic neurons and the sensory fibers type C, appears to contribute to IR CRH production in inflammatory sites. The production of CRH from the post‐ganglionic sympathetic neurons may be responsible for the stress‐induced activation of allergic/autoimmune phenomena, such as asthma and eczema, via mast cell degranulation. Antalarmin, a novel nonpeptide CRH receptor antagonist, displaced 125I‐labeled ovine CRH binding in rat pituitary, frontal cortex, and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmin significantly inhibited CRH‐stimulated ACTH release and carrageenin‐induced subcutaneous inflammation in rats. Thus, antalarmin and other related compounds that antagonize CRH at the level of its own receptor have therapeutic potential in some forms of inflammation directly mediated by type 1 CRH receptors and promise to enhance our understanding of the many roles of CRH in immune/inflammatory reactions.

Neuroendocrine-immune interactions are profoundly regulated by corticotropin-releasing hormone (CRH) indirectly, through activation of a global stress response, and directly, through pro-inflammatory actions on peripheral immune functions. The indirect effects of stress on immune/inflammatory responses occur via the stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic/adrenomedullary system. We have demonstrated that glucocorticoids and catecholamines favor T helper 2 (TH2) over T helper 1 (TH1) immune cells and mediators, by controlling the production of specific key regulatory cytokines. This could explain the influences of chronic stress on the development, course, and pathology of certain allergic, autoimmune/inflammatory, infectious, and neoplastic diseases. We have also shown that 'immune CRH' is secreted peripherally and plays a direct immunomodulatory role as an autocrine or paracrine mediator of inflammation. Upon release from immune cells and peripheral sensory afferent and/or postganglionic sympathetic nerves, CRH acts locally to elicit pro-inflammatory responses. This would explain the triggering or exacerbation of certain allergic or vasokinetic states by acute stress.

Annals of the New York Academy of SciencesVolume 816, Issue 1 p. 27-41 Autocrine—Paracrine Role of Ovarian Corticotropin-Releasing Hormone GEORGE MASTORAKOS, Corresponding Author GEORGE MASTORAKOS Endocrine Unit Evgenidion Hospital Athens University 11528, Athens, Greece DEB/National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892a Address for correspondence: Dr. George Mastorakos, Evgenidion Hospital, Endocrine Unit, Athens University, Papadiamantopoulou 20, 11528 Athens, Greece.Search for more papers by this authorLUCIA GHIZZONI, LUCIA GHIZZONI Department of Pediatrics University of Parma 43100 Parma, ItalySearch for more papers by this authorELIZABETH L. WEBSTER, ELIZABETH L. WEBSTER DEB/National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892Search for more papers by this authorGEORGE P. CHROUSOS, GEORGE P. CHROUSOS DEB/National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892Search for more papers by this author GEORGE MASTORAKOS, Corresponding Author GEORGE MASTORAKOS Endocrine Unit Evgenidion Hospital Athens University 11528, Athens, Greece DEB/National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892a Address for correspondence: Dr. George Mastorakos, Evgenidion Hospital, Endocrine Unit, Athens University, Papadiamantopoulou 20, 11528 Athens, Greece.Search for more papers by this authorLUCIA GHIZZONI, LUCIA GHIZZONI Department of Pediatrics University of Parma 43100 Parma, ItalySearch for more papers by this authorELIZABETH L. WEBSTER, ELIZABETH L. WEBSTER DEB/National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892Search for more papers by this authorGEORGE P. CHROUSOS, GEORGE P. CHROUSOS DEB/National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892Search for more papers by this author First published: 17 December 2006 https://doi.org/10.1111/j.1749-6632.1997.tb52127.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 Saffran, M., A. V. Schally & B. G. Bentey 1955. Stimulation of the release of corticotropin from the adenohypophysis by a neurohypophysial factor. Endocrinology 57: 439–444. 2 Guillemin, R. & B. Rosenberg 1955. Humoral hypothalamic control of anterior pititary: A study with combined tissue cultures. Endocrinology 57: 599–607. 3 Vale, W., J. Spiess, C. Rivier & J. Rivier 1981. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science (Washington, DC) 213: 1394–1397. 4 Fischman, A. J. & R. L. Moldow 1982. Extrahypothalamic distribution of CRF-like immunocreativity in the rat brain. Peptides (Elmsford) 1: 149–153. 5 Swanson, L. W., P. E. Sawchenko, J. Rivier & W. Vale 1983. Organization of ovine corticotropin-releasing factor immunocreactive cells and fibers in the rat brain: An immuno-histochemical study. Neuroendocrinology 36: 165–186. 6 Wynn, P. C., R. L. Hauger, M. C. Holmes, M. A. Millan, K. J. Catt & G. Aguilera 1984. Brain and pituitary receptors for corticotropin-releasing factor: Localization and differential regulation after adrenalectomy. Peptides (Elmsford) 5: 1077–1084. 7 De Souza, E. B. 1987. Corticotropin-releasing factor receptors in the rat central nervous system: Characterization and regional distribution. J. Neurosci. 7: 88–100. 8 Chrousos, G. P. & P. W. Gold 1992. The concepts of stress and stress system disorders. J. Am. Med. Assoc. 267: 1244–1252. 9 Brown, M. R., L. A. Fisher, J. Spiess, C. Rivier, J. Rivier & W. Vale 1982. Corticotropin-releasing factor: Actions on the sympathetic nervous system and metabolism. Endocrinology 111: 928–931. 10 Brown, M. R. 1991. Neuropeptide-mediated regulation of the neuroendocrine and autonomic responses to stress. In Stress, Neuropeptides and Systemic Disease. J. McCubbin, P. Kaufman & C. Nemeroff, Eds 73–93. Academic Press. New York . 11 Karalis, K., H. Sano, J. Redwine, S. Listwak, R. L. Wilder & G. P. Chrousos 1991. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science 254: 421–423. 12 Crofford, L. J., H. Sano, K. Karalis, E. L. Webster, E. A. Goldmuntz, G. P. Chrousos & R. L. Wilder 1992. Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis. J. Clin. Invest. 90: 2555–2564. 13 Crofford, L. J., H. Sano, K. Karalis, T. C. Friedman, H. R. Epps, E. F. Remmers, P. Mathern, G. P. Chrousos & R. L. Wilder 1993. Corticotropin-releasing hormone in synovial fluids and tissues of patients with rheumatoid arthritis and osteoarthritis. J. Immunol. 151: 1–10. 14 Karalis, K., G. Mastorakos, H. Sano, R. L. Wilder & G. P. Chrousos 1995. Somatostatin may participate in the antiinflammatory actions of glucocorticoids. Endocrinology 136: 4133–4138. 15 Karalis, K., G. Mastorakos, G. P. Chrousos & G. Tolis 1994. Somatostatin analogues suppress the inflammatory reaction in vivo. J Clin. Invest. 93: 2000–2006. 16 Scopa, C. D., G. Mastorakos, T. C. Friedman, M. Melachrinou, M. J. Merino & G. P. Chrousos 1994. Presence of immunoreactive corticotropin-releasing hormone in thyroid lesions. Am. J. Pathol. 145: 1159–1167. 17 Mastorakos, G., E. A. Bouzas, P. B. Silver, G. Sartani, T. C. Friedman, C. C. Chan, R. R. Caspi & G. P. Chrousos 1995. Immune corticotropin-releasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents. Endocrinology 136: 4650–4658. 18 Yoon, D. J., C. S klar & R. David 1988. Presence of immunoreactive corticotropin-releasing factor in rat testis. Endocrinology 122: 759–761. 19 Audhya, T., C. S. Hollander, D. H. Schlesinger & B. Hutchinson 1989. Structural characterization and localization of corticotropin-releasing factor in the testis. Biochem. Biophys. Acta 995: 10–16. 20 Fabbri, A., J. C. Tinajero & M. L. Dufau 1990. Corticotropin-releasing factor is produced by rat Leydig cells and has a major local antireproductive role in the testis. Endocrinology 127: 1541–1543. 21 Ulisse, S., A. Fabbri & M. L. Dufau 1989. Corticotropin-releasing factor receptors and actions in rat Leydig cells. J. Biol. Chem. 264: 2156–2163. 22 Espey, L. L. 1980. Ovulation as an inflammatory reaction: A hypothesis. Biol. Reprod. 22: 73–106. 23 Bulmer, D. 1964. The histochemistry of ovarian macrophages in the rat. J. Anat. 98: 313–319. 24 Hume, D. A., D. Halpin, H. Charlton & S. Gordon 1984. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: Macrophages of endocrine organs. Proc. Natl. Acad. Sci. USA 81: 4174–4177. 25 Katabuchi, H., Y. Fukumatsu & H. Okamura 1989. Immunohistochemical and morphological observations of macrophages in the human ovary. In Growth Factors and the Ovary. A. N. Hirshfield, Ed 409–413. Plenum. New York . 26 Adashi, E. Y. 1989. Cytokine-mediated regulation of ovarian function: Encounters of a third kind. (Editorial.) Endocrinology 124: 2043–2045. 27 Adashi, E. Y. 1990. The potential relevance of cytokines to ovarian physiology: The emerging role of resident ovarian cells of the white blood cell series. Endocrinol. Rev. 11: 454–464. 28 Erickson, G. F., D. A. Magoffin, C. A. Dyer & C. Hofeditz 1985. The ovarian androgen producing cells: A review of structure/function relationships. Endocrinol. Rev. 6: 371–399. 29 Mastorakos, G., E. L. Webster, T. C. Friedman & G. P. Chrousos 1993. Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary. J. Clin. Invest. 92: 961–968. 30 Mastorakos, G., E. L. Webster & G. P. Chrousos 1993. Corticotropin-releasing hormone and its receptors in the ovary: Physiological implications. In Intraovarian Regulators and Polycystic Ovarian Syndrome: Recent Progress on Clinical and Therapeutic Aspects. G. Tolis, J. Bringer & G. P. Chrousos, Ed Ann. N. Y. Acad. Sci. 687: 20–28. 31 Calogero, A. E., R. Bernardini, A. N. Margioris, G. Bagdy, W. T. Gallucci, P. J. Munson, L. Tamarkin, T. P. Tomai, L. Brady, P. W. Gold & G. P. Chrousos 1989. Effects of serotonergic agonists and antagonists on corticotropin-releasing hormone secretion by explanted rat hypothalami. Peptides (Elmsford) 10: 189–200. 32 Webster, E. L. & E. B. de Souza 1988. Corticotropin-releasing factor receptors in mouse spleen: Identification, autoradiographic localization, and regulation by divalent cations and guanine nucleotides. Endocrinology 122: 609–610. 33 Webster, E. L., G. Mastorakos & G. P. Chrousos 1992. Identification and characterization of corticotropin-releasing hormone receptors in rat ovary. IX Ovarian workshop “Ovarian cell interactions: Genes to Physiology.” Serono Symposia, Chapel Hill , North Carolina . 34 Mastorakos, G., C. D. Scopa, A. Vryonidou, T. C. Friedman, D. Kattis, C. Phenekos, M. J. Merino & G. P. Chrousos 1994. Presence of immunoreactive corticotropin-releasing hormone in normal and polycystic human ovaries. J. Clin. Endocrinol. Metab. 79: 1191–1197. 35 Mastorakos, G., G. Cizza, R. Kvetnansky, E. Bergamini, M. R. Blackman, P. W. Gold & G. P. Chrousos 1995. Aging and acute stress decrease corticotropin-releasing hormone in the ovary of the Fischer 344/N rat. Life Sci. 56: 1065–1071. 36 Ghizzoni, L., G. Mastorakos, A. Vottero, A. Barreca, M. Furlini, A. Cesarone, B. Ferrari, G. P. Chrousos & S. Bernasconi Corticotropin-releasing hormone-induced inhibition of steroid biosynthesis by cultured granulosa-lutein cells is mediated by interleukin-1 receptors. J. Clin. Endocrinol. Metab. Submitted. 37 Muglia, L. J., N. A. Jenkins, D. J. Gilbert, N. G. Copeland & J. A. Majzoub 1994. Expression of the mouse corticotropin-releasing hormone gene in vivo and targeted inactivation in embryonic stem cells. J. Clin. Invest. 93: 2066–2072. 38 Asakura, H., I. Zwain & S. S. C. Yen 1996. Gene expression and cellular localization of corticotropin-releasing factor (CRF), CRF-binding protein (CRF-BP) and type-1 CRF receptors (CRF-R) in the human ovary. 10th International Congress of Endocrinology, San Francisco , CA . 39 Stephanou, A., D. S. Jessop, R. A. Knight & S. L. Lightman 1990. Corticotropin-releasing factor-like immunoreactivity and mRNA in human leukocytes. Brain Behav. Immun. 4: 67–73. 40 Merchenthaler, I., M. A. Hynes, S. Vigh, A. V. Schally & P. Petrusz 1983. Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat spinal cord. Brain Res. 275: 373–377. 41 Udelsman, R., J. P. Harwood, M. A. Millan, G. P. Chrousos, D. S. Goldstein, R. Zimlichman, K. J. Catt & G. Aguilera 1986. Functional corticotropin-releasing factor receptors in the primate peripheral sympathetic nervous system. Nature (London) 319: 147–150. 42 Nappi, R. E. & S. Rivest 1996. Stress-induced genetic expression of a selective corticotropin-releasing factor-receptor subtype within the rat ovaries: An effect dependent on the ovulatory cycle. Biol. Reprod. 53: 1417–1428. 43 Chrousos, G. P., J. Bringer & G. Tolis 1993. Introduction. In Intraovarian Regulators and Polycystic Ovarian Syndrome: Recent Progress on Clinical and Therapeutic Aspects. G. Tolis, J. Bringer, G. P. Chrousos, Eds Ann. N. Y. Acad. Sci. 687: xiii–xv. 44 Vamvakopoulos, N. C. & G. P. Chrousos 1993. Evidence of direct estrogen regulation of human corticotropin-releasing hormone gene expression: Potential implications for the sexual dimorphism of the stress response and immune/inflammatory reaction. J. Clin. Invest. 92: 1896–1902. 45 Burgess, L. H. & R. J. Handa 1992. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion and glucocorticoid receptor-mediated functions in female rats. Endocrinology 131: 1261–1269. 46 Kavelaars, A., R. E. Ballieux & C. J. Heijnen 1989. The role of IL-1 in the corticotropin-releasing factor and arginine-vasopressin-induced secretion of immunoreactive β-endorphin by human peripheral blood mononuclear cells. J. Immunol. 142: 2338–2342. 47 Hurwitz, A., D. W. Payne, J. N. Packman, C. L. Andreani, C. E. Resnick, E. R. Hernandez & E. Y. Adashi 1991. Cytokine-mediated regulation of ovarian function: Interleukin-1 inhibits ganodotropin-induced androgen biosynthesis. Endocrinology 129: 1250–1256. Citing Literature Volume816, Issue1Adolescent Gynecology and Endocrinology: Basic and Clinical AspectsJune 1997Pages 27-41 ReferencesRelatedInformation

Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator. CRH receptors (CRH-R1, R2alpha, R2beta) exhibit a specific tissue distribution. Antalarmin, a novel pyrrolopyrimidine compound, displaced 12SI-oCRH binding in rat pituitary, frontal cortex and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmnin (20 mg/kg body wt.) significantly inhibited CRH-stimulated ACTH release and carageenin-induced subcutaneous inflammation in rats. Antalarmin, or its analogs, hold therapeutic promise in disorders with putative CRH hypersecretion, such as melancholic depression and inflammatory disorders.