Pescatore Robyn, Marrone Gina F, Sedberry Seth, Vinton Daniel, Finkelstein Netanel, Katlowitz Yitzchak E, Pasternak Gavril W, Wilson Krista R, Majumdar Susruta
†Department of Chemistry, Wingate University, PO Box 159, Wingate, North Carolina 28174, United States.
‡Department of Neuroscience, Weil Cornell Medical College, 1300 York Avenue, New York, New York 10065, United States.
ACS Chem Neurosci. 2015 Jun 17;6(6):905-10. doi: 10.1021/acschemneuro.5b00060. Epub 2015 Apr 14.
Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.
强啡肽是由巨型叶泡蛙（Phyllomedusa bicolor）皮肤天然产生的肽类。它们是δ-阿片受体选择性激动剂。在此，我们报告了基于[d-Ala(2)]强啡肽II模板设计并合成的一种肽Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3（GATE3-8），其在体外放射性配体结合试验中对μ-和κ-阿片受体具有δ选择性。在[(35)S]GTPγS功能试验中它是一种完全激动剂，对小鼠进行脊髓上给药时具有镇痛作用。3（GATE3-8）的镇痛作用被选择性δ受体拮抗剂纳曲吲哚阻断，表明3的镇痛作用是由δ-阿片受体介导的。我们制备了一种将(125)I掺入3（GATE3-8）的放射性配体。该放射性配体在中国仓鼠卵巢（CHO）细胞中表达δ受体时的解离常数KD为0.1 nM。此外，通过在Phe(3)芳香环的对位引入各种卤素，合成了一系列基于3（GATE3-8）的肽。对这些肽在μ-、δ-和κ-阿片受体上的结合亲和力进行了表征，结果显示结合亲和力与卤素取代基的大小之间存在线性关系。这些肽可能是用于探究δ-阿片受体药理学的有趣工具。
