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Reduction of stress hormone responses by the CRF1 receptor antagonist, NBI-34041
Abnormalities of the hypothalamic-pituitary-adrenocortical (HPA) axis, such as increased plasma cortisol levels are found in depression. Corticotropin releasing factor (CRF) is hypersecreted in depression which led to the suggestion that a blockade of the CRF system could have a beneficial effect in major depressive and anxiety related disorders. CRF acts at two subtypes of G-protein coupled receptors (CRF1 and CRF2). Since human CRF binds at the CRF1 receptor with 15-fold higher affinity over the CRF2 receptor, selective CRF1 receptor antagonists have been sought as new antidepressants. A novel nonpeptide CRF1 receptor antagonist, NBI-34041/SB723620, has been studied preclinically and clinically. In vitro experiments with different cell lines expressing human CRF receptors have shown that NBI-34041 is a high affinity and selective CRF1 receptor antagonist. In vivo studies in rats have indicated that NBI-34041 attenuates the release of adrenocorticotropic hormone (ACTH) induced by CRF or stress (intermittent footshock). A clinical Phase I study in 24 healthy male subjects showed that NBI-34041 for 14 days did not modify diurnal plasma ACTH and cortisol secretion or plasma ACTH and cortisol responses evoked by intravenous administration of 100 g of human CRF. In contrast NBI-34041 attenuated the psychosocial stress response measured with the Trier Social Stress Test (TSST). These preclinical and clinical data show that the CRF1 receptor antagonist, NBI-34041, can reduce the hormonal response to stress both in animals and humans without impairing basal regulation of the HPA system. Phase II studies of NBI-34041 are awaited with interest.

Ising M, Zimmermann US, Kunzel HE, Uhr M, Foster AC, Learned-Coughlin SM, Holsboer F, Grigoriadis DE (2007). High-affinity CRF(1) receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology advance online publication, 7 February; doi:10.1038/sj.npp.1301328.
Updated February 2007

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