Nonpeptide Corticotropin-Releasing Hormone Receptor Type 1 Antagonists and Their Applications in Psychosomatic Disorders

Abstract

Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in ‘somatic’ disorders. Some rare forms of Cushing’s disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of ‘psychosomatic’ disorders.

High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts

“…12 However, the statistical evidence of association in our study (lowest p = 0.0007) is the first suggestion that SCN3B may be involved in oral clefts. The CRHR1 gene product binds to corticotropin-releasing hormone, 29 while MAPT transcripts are differentially expressed in the nervous system. 30 Although these genes are homologs of genes in the mouse clf1 region, 13 and both are expressed during craniofacial development, neither has been suggested to control risk for oral clefts.…”

Aspectos emocionais associados a disfunções gastroenterológicas

“…Inúmeros estudos têm demonstrado que os níveis de estresse, ansiedade e depressão em que o sujeito se encontre podem acarretar maior vulnerabilidade a doenças, uma vez que as defesas imunológicas ficam rebaixadas ou, em casos mais graves, destruídas, agravando o quadro da patologia (Contoreggi, Rice & Chrousos, 2004;Levenstein, 1999;Overmier & Murison, 2005;Stern, 2003).…”

Cushing’s Disease, Hypertension, and Other Sequels

“…26 The CRH receptor has become a drug target that could play a role in the treatment of depression. 27 Investigations of CRH type 1 receptor nonapeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. Cushing's disease and related pituitary/ adrenal disorders could become obvious applications for CRH type 1 receptor antagonists.…”