Target Background

The corticotropin-releasing hormone receptor 1 (CRHR1) is a class B G-protein-coupled receptor (GPCR) that mediates the actions of the neuropeptide hormone corticotropin-releasing hormone (CRH). CRHR1 is widely expressed in the anterior pituitary gland, with additional expression in key brain regions such as the amygdala, hippocampus, and cerebral cortex, as well as in peripheral tissues including the immune system, gastrointestinal tract, and cardiovascular system. Its tissue distribution reflects its central role in initiating the endocrine, autonomic, and behavioral responses to stress.

Upon binding to CRH, CRHR1 couples predominantly to Gs proteins, stimulating adenylate cyclase and elevating intracellular cAMP levels. This leads to activation of downstream effectors such as protein kinase A (PKA). In the anterior pituitary, CRHR1 signaling stimulates the synthesis and release of adrenocorticotropic hormone (ACTH), which subsequently drives cortisol production from the adrenal cortex. Beyond the pituitary, CRHR1 activity in the brain coordinates anxiety-related behaviors, modulates learning and memory, and regulates appetite, while in the periphery it influences immune function, gut motility, and cardiovascular tone.

Pharmacologically, CRHR1 has been a long-standing target for stress-related psychiatric disorders. Antagonists of CRHR1 have been extensively investigated for major depressive disorder and anxiety disorders due to their ability to dampen an overactive hypothalamic-pituitary-adrenal (HPA) axis. Early clinical proof-of-concept was provided by the antagonist R121919, which demonstrated anxiolytic and antidepressant effects. More recent research has continued to explore antagonists like verucerfont for conditions such as post-traumatic stress disorder. With its pivotal role in the central stress response and its integration of neuroendocrine and behavioral outputs, CRHR1 remains a major focus for the development of novel neuropsychiatric therapeutics.