Recent advances with the CRF1 receptor: Design of small molecule inhibitors, receptor subtypes and clinical indications

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 we ll as the discovery of non-peptide receptor antagonists for CRF receptors h ave begun a new era of CRF study. Presently, there are five distinct target s 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 C RF2 alpha CRF2 beta and CRF2 gamma. The pharmacology and localization of al l of these proteins in brain has been well established. The CRF1 receptor s ubtype is localized primarily to cortical and cerebellar regions while the CRF2 alpha receptor is localized to subcortical regions including the later al septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF2 beta receptor is primarily localized to heart, skeletal muscle an d in the brain, to cerebral arterioles and choroid plexus. The CRF2 gamma r eceptor has most recently been identified in human amygdala. Expression of these receptors in mammalian cell lines has made possible the identificatio n of non-peptide, high affinity, selective receptor antagonists. While the natural mammalian ligands oCRF and r/hCRF have high affinity for the CRF1 r eceptor subtype, they have lower affinity for the CRF2 receptor family maki ng them ineffective labels for CRF2 receptors. [I-125]Sauvagine has been ch aracterized as a high affinity ligand for both the CRF1 and the CRF2 recept or subtypes and has been used in both radioligand binding and receptor auto radiographic studies as a tool to aid in the discovery of selective small m olecule receptor antagonists. A number of non-peptide CRF1 receptor antagon ists that can specifically and selectively block the CRF1 receptor subtype have recently been identified. Compounds such as CP 154,526 (12), NBI 27914 (129) and Antalarmin (154) inhibit CRF-stimulation of cAMP or CRF-stimulat ed ACTH release from cultured rat anterior pituitary cells. Furthermore, wh en administered peripherally, these compounds compete for er vivo [I-125]sa uvagine binding to CRF1 receptors in brain sections demonstrating their abi lity to cross the blood-brain-barrier. In ill vivo studies, peripheral admi nistration of these compounds attenuate stress-induced elevations in plasma ACTH levels in rats demonstrating that CRF1 receptors can be blocked in th e periphery. Furthermore, peripherally administered CRF1 receptor antagonis ts have also been demonstrated to inhibit CRF induced seizure activity. The se data clearly demonstrate that non-peptide CRF1 receptor antagonists, whe n 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, t hese molecules will prove useful in the discovery and development of potent ial orally active therapeutics for these disorders.