Chapter 5. Corticotropin-Releasing Hormone (CRH) Receptors and the Discovery of Selective Non-Peptide CRH1 Antagonists

Abstract

Publisher Summary There is a serious unmet medical need for new neuropsychiatric drugs that are mechanistically distinct from existing therapeutic agents. Large patient subpopulations do not respond well or tolerate well current anxiolytics or anti-depressant drugs. The need is more urgent for other related affective disorders, such as obsessive-compulsive disorder, anorexia nervosa, post-traumatic stress disorder, and drug withdrawal. The primacy of corticotropin-releasing hormone (CRH) as regulator of the hypothalamus pituitary adrenal (HPA) axis suggests that agents acting at CRH receptors or the CRH binding protein may have profound therapeutic effects in these disorders. Receptors for corticotropin releasing hormone have become targets for drug design, because dysfunction in the HPA axis has been correlated with various diseases. Two subtypes of CRH receptors are known, one of which has splice variants, and a CRH binding protein. The receptor subtypes are G-protein coupled receptors that are distinguished by the rank order of potencies of peptide agonists in a CRH-coupled adenylate cyclase assay and by their anatomical localization. The CRH1 receptor, which consists of 415 amino acids, is positively coupled to adenylate cyclase and is primarily expressed in the rat cortex, hypothalamus, amygdala, cerebellum, and pituitary. In recent times, significant progress has been made in defining the roles of CRH receptor subtypes and the binding protein in disease through studies on knockout and transgenic mice as well as the discovery of peptidic and nonpeptidic antagonists, some of which are likely to be used as therapeutic agents. This chapter discusses such recent developments in CRH molecular biology, pharmacology, clinical data, and drug design studies.