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.

authors

Zorrilla EP,Koob GF

doi

10.1517/13543784.13.7.799

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

799-828

issue

7

eissn

1354-3784

issn

1744-7658

pii

EID130706

journal_volume

13

pub_type

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