James R. McCarthy*, Stephen C. Heinrichs and Dimitri E. Grigoriadis Pages 289 - 315 ( 27 )
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 CRF<sub>1</sub> and CRF<sub>2 </sub> receptors (belonging to the superfamily of G-protein coupled receptors) and the CRF-binding protein. The CRF<sub>2 </sub> receptor exists as three splice variants of the same gene and have been designated CRF<sub>2α</sub> CRF<sub>2β</sub> and CRF<sub>2γ-</sub> The pharmacology and localization of all of these proteins in brain has been well established. The CRF <sub>I</sub> receptor subtype is localized primarily to cortical and cerebellar regions ·while the CRF<sub>2α</sub> receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF<sub>2β</sub> receptor is primarily localized to heart, skeletal muscle and in the brain, to cerebral arterioles and choroid plexus. The CRF<sub>2γ</sub> receptor has most recently 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 CRF<sub>2 </sub> receptor family making them ineffective labels for CRF<sub>2 </sub> receptors. [<sup>125</sup>I]Sauvagine has been characterized as a high affinity ligand for both the CRF<sub>1</sub>and the CRF<sub>2 </sub> 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 CRF<sub>1</sub> receptor antagonists that can specifically and selectively block the CRF<sub>1</sub> 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 [<sup>125</sup>I]sauvagine binding to CRF <sub>I</sub> 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 CRF<sub>1</sub> receptors can be blocked in the periphery. Furthermore, peripherally administered CRF<sub>1</sub> receptor antagonists have also been demonstrated to inhibit CRF-induced seizure activity. These data clearly demonstrate that non-peptide CRF<sub>1</sub> receptor antagonists, when administered systemically, can specifically block central CRF<sub>1</sub> receptors and provide tools that can be used to determine the role o f CRF<sub>1</sub> 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.