The therapeutic potential of CRF1 antagonists for anxiety

Abstract

Preclinical studies suggest that the brain corticotropin-releasing factor (CRF) systems mediate anxiety-like behavioural and somatic responses through actions at the CRF₁ receptor. CRF₁ antagonists block the anxiogenic-like effects of CRF and stress in animal models. Cerebrospinal fluid levels of CRF are elevated in some anxiety disorders and normalise with effective treatment, further implicating CRF systems as a therapeutic target. Prototypical CRF₁ antagonists are highly lipophilic, non-competitive antagonists of peptide ligands. Modification of the chemotype and the identification of novel pharmacophores are yielding more drug-like structures with increased hydrophilicity at physiological pHs. Newer compounds exhibit improved solubility, pharmacokinetic properties, potency and efficacy. Several clinical candidates have entered Phase I/II trials. However, unmet challenges await resolution during further discovery, clinical development and therapeutic application of CRF₁ antagonists.

• anxiety
• anxiolytic
• corticotropin-releasing factor receptor antagonist
• corticotropin-releasing hormone receptor antagonist
• depression
• nonpeptide
• small molecule
• stress