The recent development of a small molecule corticotropin-releasing hormone receptor 1 (CRHR1) antagonist has provided important information on the contribution of this receptor to the development of stress-related diseases. With extensive experience in drug development, Creative Biolabs has established a comprehensive and systematical technology platform to provide global customs with high-quality psychotropic drug development services to promote the basic research and clinical therapeutics of psychiatric diseases.
Introduction to Corticotrophin-Releasing Hormone (CRH)
CRH is a 41-amino acid neuropeptide secreted by the paraventricular nucleus of the hypothalamus. CRH and its receptors are also found in many extra-hypothalamic sites of the central nervous system (CNS). In the CNS, CRH plays a major coordinative role for the stress response, including activation of the arousal and sympathetic systems, central suppression of the immune system, and elicitation of stress-related behaviors. CRH is the main member of a family of neuropeptides that includes the human urocortins (Ucn1, Ucn2 or stresscopin-related peptide, and Ucn3 or stresscopin), as well as fish urotensin I and frog sauvagine.
Clinical Implications of CRHR Antagonists
Orally available nonpeptidic small molecules that can cross the blood-brain barrier have been discovered. Some of these have entered clinical development. The following compounds have particularly aroused great interest: CP-154,526 and its methyl analog antalarmin, R-121919, R-278995, DMP-696, and DMP-904, SSR-125543A, NBI-35 965, NBI-30775/R121919, and NBI34041.
Major depression and anxiety, conditions that are related to HPA hyperactivity are good targets for nonpeptidic CRH antagonists. NBI-30775/R121919 was found to have a clinical profile comparable to that of paroxetine. Administration of NBI-34041 to healthy controls reduced the stress-elicited secretion of stress hormones. Neither compound impaired the CRH-induced ACTH and cortisol release. From these studies, the authors conclude that both antagonists have psychotropic effects unrelated to their neuroendocrine action, in line with behavioral data obtained from transgenic mice with CRH gene deletions. In an open-label clinical trial, R121919 reduced measures of anxiety and depression in patients with major depression, which then relapsed when drug administration was discontinued. Based on these reports, NBI34041 and other CRHR1 antagonists could be used to prevent the development of stress-related disorders such as depression, anxiety, and posttraumatic stress disorder.
The behavioral and physiological manifestations of drug withdrawal and the relapse to drug-taking behavior induced by environmental stressors seem to be strongly related to the activity of extra-hypothalamic brain CRH systems. CP-154,526 attenuates stress-induced relapse to drug-seeking in rats induced by footshock. These results extend previous reports on the role of CRH in the reinstatement of drug-seeking induced by stressors. Antalarmin reversed the place aversion produced by precipitated opiate withdrawal similar to buprenorphine, suggesting a therapeutic potential in opiate dependence.
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With proven expertise in psychiatric disease research, Creative Biolabs aspires to become a fully integrated biopharmaceutical company focused on every link of psychotropic drug development. Our professional scientists will customize optimal experimental schemes and help with every problem.
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CRH receptor antagonist is one of the most important HPA-axis antagonists applied in the target development of psychiatric disorders. With extensive experience accumulated from hundreds of successful precedents, Creative Biolabs offers high-quality and comprehensive psychotropic drug development services to global researchers. If you have other questions, please feel free to contact us.
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