Recent Advances with the CRF1 Receptor: Design of Small Molecule Inhibitors, Receptor Subtypes and Clinical Indications
Authors: McCarthy James R. , Heinrichs Stephen C. , Grigoriadis Dimitri E. 
Published: January 2023

Corticotropin-releasing factor (CRF) has been widely implicated as playing a major role in modulating the endocrine, autonomic, behavioral and immune responses to stress. The recent cloning of multiple receptors for CRF as well as the discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of CRF study. Presently, there are five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These
fall into three distinct classes, encoded by three different genes and have been termed the CRF1 and CRF2 receptors (belonging to the superfamily of G-protein coupled receptors) and the CRF-binding protein. The CRF2 receptor exists
as three splice variants of the same gene and have been designated CRF2α CRF2β and CRF2γ- The pharmacology and localization of all of these proteins in brain has been well established. The CRF I receptor subtype is localized primarily to cortical and cerebellar regions ·while the CRF2α receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF2β receptor is primarily
localized to heart, skeletal muscle and in the brain, to cerebral arterioles and choroid plexus. TheCRF2γ receptor has
most recen\ly been identified in human amygdala. Expression of these receptors in mammalian cell lines has made possible the identification of non-peptide, high affinity, selective receptor antagonists. While the natural mammalian
ligands oCRF and r/hCRF have high affinity for the CRF I receptor subtype, they have lower affiruty for the CRF2 receptor family making them ineffective labels for CRF2 receptors. [125I]Sauvagine has been characterized as a high
affinity ligand for both the CRF1 and the CRF2 receptor subtypes and has been used in both radioligand bindii:ig and receptor autoradiographic studies as a tool to aid in the discovery of selective small molecule receptor antagonists. A number of non-peptide CRF1 receptor antagonists that can specifically and selectively block the CRF1 receptor subtype have recently been identified. Compounds such as CP 154,526 (12), NB! 279 l 4 (129) and Antalarmin (154) inhibit CRF-stimulation of cAMP or CRF-stimulated ACTH release from cultured rat anterior pituitary cells.
Furthermore, when administered peripherally, these compounds compete for ex vivo [125l]sauvagine binding to CRF I
receptors in brain sections demonstrating their ability to cross the blood-brain-barrier. ln in vivo studies, peripheral administration of these compounds attenuate stress-induced elevations in plasma ACTH levels in rats demonstrating
that CRF1 receptors can be blocked in the periphery. Furthermore, peripherally administered CRF1 receptor
antagonists have also been demonstrated to inhibit CRF-induced seizure activity. These data clearly demonstrate \hat
non-peptide CRF1 receptor antagonists, when administered systemically, can specifically block central CRF1 receptors and provide tools that can be used to determine the role of CRF1 receptors in various neuropsychiatric and neurodegenerative disorders. In addition, these molecules will prove useful in the discovery and development of
potential orally active therapeutics for these disorders.