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 µg 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