Abstract
Evidence has been accumulated suggesting that CRF mediates the endocrine, autonomic, behavioral and immune responses to stressful stimuli. Immunohistochemical and anatomical data supported the notion that this peptide fulfills all of the characteristics of a bona fide neurotransmitter. CRF exerts its actions through interaction with multiple CRF receptor binding sites. The cloning of these multiple receptors for CRF as well as the recent discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of study for this neurotransmitter. The receptors for CRF fall into two distinct classes encoded by two different genes and have been termed the CRF1 and CRF2 receptors belonging to the superfamily of the class B G-protein coupled receptors. Heterologous expression of the human receptors in mammalian cell lines has made possible the identification of non-peptide, high affinity, and selective receptor antagonists. These compounds which can functionally inhibit the actions of CRF on the in vitro stimulation of cAMP or ACTH release from cultured rat anterior pituitary cells. In addition, they attenuate CRF or stress-induced elevations in plasma ACTH levels in rats demonstrating that pituitary CRF1 receptors can be blocked. When administered systemically, these compounds cross the blood-brain-barrier and interact directly with central CRF1 receptors in brain regions rich with this subtype as evidenced by ex vivo receptor autoradiography. While the discovery of specific or selective CRF2 receptor antagonists has not yet been forthcoming, a great deal of evidence is emerging that suggests that CRF1 receptor antagonists will prove useful in the discovery and development of potential orally active therapeutics for various neuropsychiatric disorders.
Published Version
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