Corticotropin-releasing factor receptor 1 (CRHR1) (CRHR1)

Corticotropin-releasing factor receptor 1 (CRHR1) is a Class B G protein-coupled receptor that serves as a primary mediator of the neuroendocrine stress response (UniProt: P34998). Predominantly expressed in the anterior pituitary gland and the central nervous system, CRHR1 binds with high affinity to corticotropin-releasing hormone (CRH) secreted by the hypothalamus (NCBI Gene: 1394). Upon activation, it stimulates the production and release of adrenocorticotropic hormone (ACTH), which subsequently triggers cortisol secretion from the adrenal cortex as part of the hypothalamic-pituitary-adrenal (HPA) axis (PubMed: 15635406). Dysregulation of the CRHR1 pathway is strongly linked to psychiatric conditions such as major depressive disorder and generalized anxiety, as well as endocrine disorders like congenital adrenal hyperplasia (CAH) (PubMed: 32603451). Therapeutic strategies focus on CRHR1 antagonists, such as crinecerfont and tildacerfont, to reduce ACTH-driven androgen excess in CAH or to mitigate stress-related symptoms in mood disorders (ClinicalTrials.gov: NCT04452318). Despite its potential, clinical development has faced hurdles including variable efficacy in psychiatric indications and concerns regarding liver toxicity with certain chemical scaffolds (PubMed: 21338472).

Other names

CRF-R1CRFR1CRH-R1Corticotropin-releasing hormone receptor 1CRF1 receptor

Small-molecule antagonism of the CRHR1 receptor to block the binding of endogenous corticotropin-releasing hormone (CRH), thereby inhibiting the downstream signaling cascade that leads to the synthesis and secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (PubMed: 32603451, 33164385).