Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
Drug Discov Today. 2010 May;15(9-10):371-83. doi: 10.1016/j.drudis.2010.02.011. Epub 2010 Mar 3.
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.
自 1981 年分离应激分泌肽以来,人们一直在寻找促肾上腺皮质释放因子 (CRF) 受体拮抗剂。虽然关于 CRF(1) 拮抗剂作为抗抑郁药的疗效的证据不一,但 CRF(1) 拮抗剂可能是焦虑和成瘾的新型药物治疗方法。对 CRF 家族受体配体-受体相互作用的双域模型的理解的进展可能会产生化学上新颖的 CRF(1) 受体拮抗剂,包括肽 CRF(1) 拮抗剂、具有信号转导选择性的拮抗剂和通过细胞外 (而不是跨膜) 结构域起作用的非肽 CRF(1) 拮抗剂。已经鉴定出符合流行药效基团并表现出类似药物的药代动力学特性的新型配体。CRF(1) 拮抗剂的治疗效用应该很快就会更清楚:目前有几种小分子正在进行抑郁症、焦虑症和肠易激综合征的 II/III 期临床试验。