CRF Antagonists

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In addition to the mimicry in the responses triggered by stress and central injection of CRF, the evidence for a role of brain CRF-signaling pathways in the stress response came from studies using CRF receptor antagonists injected into the cerebrospinal fluid. Among the specific nonselective CRF1/CRF2 antagonists are a-helical CRF9-41 (88), D-Phe12CRF12-41 (89), and the recently developed, more potent and long acting peptides, astressin (90,91) and astressin B (92).

The potential therapeutic application of CRF1 receptor antagonists for the treatment of neuropsychiatric disorders, such as anxiety and depression (93-95), led to synthetic nonpep-tide selective CRF1 antagonists that cross the blood-brain barrier (96,97). These include CP-154,526 (97), antalarmin (98), NBI-30775 (formerly R-121919) (99), and the water-soluble compound, NBI-35965 (49,99), and several others (96,100). These CRFX antagonists have high brain penetrance upon peripheral, including oral, administration (49,99).

The wealth of evidence based on pharmacologic and genetic approaches clearly indicates that the activation of the brain CRF1 receptor subtype plays a predominant role in stress-related endocrine (activation of the HPA axis with the release of ACTH and glucocorticoids) (14), behavioral (anxiety and depression) (95), and autonomic (activation of sympathetic and sacral parasympathetic outflow) (101,102) responses as well as gut motor alterations (stimulation of colonic motor function and diarrhea) (15). Recently, selective peptide CRF2 receptor antagonists, namely, antisauvagine-30, K41498, [D-Phe11,His12,Nle17]sauvaginen-40, and the more potent, long acting analog, astressin2-B, have been developed (103,104). Although the role of CRF2 receptors in the stress response still needs to be further defined, existing reports indicate that the activation of peripheral CRF2 receptors diminishes brain CRF1-mediated endocrine, cardiovascular, and visceral responses (14,105-108).

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