The discovery of selective modulators of the glucocorticoid receptor (GR) has become an area of considerable interest in the past decade, and although much of this effort has been directed toward dissociated GR agonists as antiinflammatory agents, significant progress has also been made in the GR antagonist arena. With extensive experience in psychotropic drug development, Creative Biolabs has been focused on GR antagonists’ application in psychiatric disorders for years. Years of accumulation and hundreds of successful precedents make us capable of providing global customers with high-quality target development services for psychiatric disorders.
Introduction to Glucocorticoid Receptor
GR is part of the nuclear hormone receptor subfamily of oxosteroids that includes the mineralocorticoid (MR), progesterone (PR), and androgen (AR) receptors. The estrogen receptor (ER), which principally binds the aromatic A-ring steroid estradiol, is a distinct but closely related subfamily. Similar to other nuclear hormone receptors, GR is comprised of three major functional domains: 1) an N-terminal extension that contains an activation function (AF1); 2) a central DNA binding region; and 3) a C-terminal ligand-binding domain (LBD).
Therapeutic Applications of GR Antagonists in Psychiatric Disease
Symptoms of psychotic depression include severe depression and psychotic features including hallucinations and delusions. Treatment with traditional antidepressants and antipsychotic agents is not generally effective and is fraught with significant side effects. Electroconvulsive therapy (ECT) is considered an effective therapy for psychotic depression but is associated with memory loss and cognitive impairment, in addition to being very expensive. Acute (4-8 day) treatment with mifepristone is an effective treatment for psychotic depression, especially in alleviating the psychotic symptoms and the clinical experience has been reviewed. Moreover, the effect of GR antagonism on the neurochemical responses elicited by selective serotonin reuptake inhibition (SSRI) was studied in the rat. Administration of steroidal GR antagonists enhanced fluoxetine-induced increase in basal serotonin (5-HT) levels and led to more rapid desensitization of 5-HT1A autoreceptors. These results suggest that concurrent GR antagonist therapy could decrease the delay in onset of action typically observed with SSRI antidepressant therapy.
Antagonism of GR, either with mifepristone or GR antisense oligonucleotides, has been shown to reduce neuropathic pain responses (thermal hyperalgesia and mechanical allodynia) in rodent chronic constriction nerve injury models (CCI). The antinociceptive effects appear to be mediated by GR in the spinal cord, as intrathecal or intraperitoneal administration of mifepristone was effective, whereas intracerebroventricular injection was not. The underlying mechanisms of GR antagonist activity against neuropathic pain have been suggested to involve GR-mediated reduction in N-type voltage-dependent calcium channel signal transduction and GR modulation of NMDA receptor expression and function.
Services at Creative Biolabs
Having focused on drug development for years, Creative Biolabs has accumulated extensive professional experience in the target development of psychiatric disorders. We are technologically mature in every part of the target development including the discovery, in vivo/ in vitro activity detection, psychiatric disorder animal model development, and manufacturing. Moreover, our experts specialized in psychotropics will help to solve every problem you meet during the process of target development.
Why Us?
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Efficient, accurate, and cost-effective
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Reliability and information security
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Extensive experience and hundreds of successful precedents
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Comprehensive technology platform with an excellent expert team
GR antagonist has shown its potential in the application of psychotropic drug development. Based on extensive industrial experience accumulated from hundreds of successful precedents and years of research in drug development, Creative Biolabs offers high-quality and worry-free target development services to global customers. If the above services do not meet your requirements, please contact us for your exclusive solution.
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