设计具有阿片样物质激动剂活性和胆囊收缩素拮抗剂活性的新型肽配体用于治疗疼痛。
Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain.
作者信息
Hruby V J, Agnes R S, Davis P, Ma S-W, Lee Y S, Vanderah T W, Lai J, Porreca F
机构信息
Department of Chemistry, University of Arizona, Tucson 85721, USA.
出版信息
Life Sci. 2003 Jun 27;73(6):699-704. doi: 10.1016/s0024-3205(03)00390-4.
Abstract
Disease states such as neuropathic pain offer special challenges in drug design due to the system changes which accompany these diseases. In this manuscript we provide an example of a new approach to drug design in which we have modified a potent and selective peptide ligand for the CCK-2 receptor to a peptide which has potent agonist binding affinity and bioactivity at delta and mu opioid receptors, and simultaneous antagonist activity at CCK receptors. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH(2) (i.e., RSA 601) which have the designed properties.
摘要
诸如神经性疼痛等疾病状态，由于伴随这些疾病出现的系统变化，在药物设计方面带来了特殊挑战。在本手稿中，我们提供了一个药物设计新方法的实例，即我们已将一种对CCK - 2受体具有强效且选择性的肽配体修饰为一种在δ和μ阿片受体上具有强效激动剂结合亲和力和生物活性，同时在CCK受体上具有拮抗剂活性的肽。基于重叠药效团概念的从头设计是该设计的核心假设，并由此产生了具有所设计特性的化合物，如H - Tyr - D - Phe - Gly - D - Trp - NMeNle - Asp - Phe - NH₂（即RSA 601）。
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