Progress in corticotropin-releasing factor-1 antagonist development.
Corticotropin releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF(1) antagonists as antidepressants, CRF(1) antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand-receptor interactions for CRF family receptors might yield chemically novel CRF(1) receptor antagonists, including peptide CRF(1) antagonists, antagonists with signal transduction selectivity and nonpeptide CRF(1) antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to the prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF(1) antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome.
Zorrilla
Eric P
EP
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. ezorrilla@scripps.edu
Koob
George F
GF
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010330:Patents as Topic; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D019966:Substance-Related Disorders / Q000188:drug therapy; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D015507:Drugs, Investigational; D008024:Ligands; D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone