R27899s Cra0450

SSR 125543 fiBt 30545

Fig. 1. Non-peptidergic CRF, antagonists: comparable scaffold (black), different amines (red). The majority of compounds presented here are bicyclic.

NBI35965, or SSR125543A, are orally bioavailable and penetrate into the brain (Habib et al, 2000; Keck et al., 2001; Gully et al., 2002; Heinrichs et al., 2002; Keller et al, 2002; Chaki et al, 2003; Million et al, 2003 Fig. 2). More recently, the synthesis of potential CRFi PET ligands for in vivo imaging has been reported: [UC]R121920 and [76Br]MJL-l-109-2 (Jagoda et al, 2003; Kumar et al, 2003). These compounds will be of value for the determination of the degree of receptor occupancy required to obtain clinical responses in humans.

Neuroendocrine effects of CRFj antagonists

Given that the CRF, receptor predominates at the pituitary level and is also expressed at the adrenal level, one pertinent question is whether HPA axis activity is affected by administration of a CRF, antagonist. This clearly is the case as both CRF- or stress-induced ACTH or corticosterone release are blocked by a number of CRF! antagonists (Schulz et al, 1996; Smagin et al, 1998; Habib et al, 2000; Gully et al, 2002; Heinrichs et al, 2002; McElroy et al, 2002), while basal plasma ACTH level has been reported to remain unaffected after acute administration in the majority of studies (Schulz et al, 1996; Smagin et al, 1998; Broadbear et al, 2002; Maciag et al, 2002). Surprisingly, antalarmin had no effect on inescapable shock-induced increases in plasma ACTH and corticosterone, but blocked the rise in plasma ACTH following exposure to foot shock (Deak et al, 1999). One study also reported that CRF, blockade with SSR125543A partially diminished basal plasma ACTH levels in conscious rats 2 h after oral administration to about 50% of basal levels (Gully et al, 2002). Importantly, however, the HPA axis is not completely shut down after CRF] blockade and reactivity to stress remains even under conditions of CRF] antagonism (Deak et al, 1999; Heinrichs et al, 2002). This suggests that escape routes to maintain ACTH release exist, e.g., mediated by vasopressin, and that some of the basic functions of the HPA axis would not be hindered by this treatment approach.

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