Yamamoto Takashi, Nair Padma, Davis Peg, Ma Shou-wu, Navratilova Edita, Moye Sharif, Tumati Suneeta, Lai Josephine, Vanderah Todd W, Yamamura Henry I, Porreca Frank, Hruby Victor J
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 2007 Jun 14;50(12):2779-86. doi: 10.1021/jm061369n. Epub 2007 May 22.
A series of bifunctional peptides that act as agonists for delta and mu opioid receptors with delta selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at delta/mu opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3) 2 (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)2 (7) had excellent agonist activity for both delta opioid and mu opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.
设计并合成了一系列双功能肽，这些肽作为具有δ选择性的δ和μ阿片受体激动剂以及神经激肽-1（NK1）受体拮抗剂，有望作为镇痛药应用于各种疼痛状态。使用放射性配体结合测定法以及利用细胞膜和动物组织的功能测定法对这些肽进行了表征。对作为两种受体识别的地址部分的第五个残基进行了优化。它对δ/μ阿片受体和NK1受体的活性都有关键影响。在合成的肽中，H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3)2（5）和H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)2（7）对δ阿片受体和μ阿片受体均具有出色的激动剂活性，对NK1受体具有出色的拮抗剂活性。这些结果表明，可以实现具有阿片激动剂和神经激肽-1拮抗剂活性的多功能配体的合理设计，并且可能为治疗慢性疼痛和多种疼痛状态提供一种新工具。
