Synthesis and Pharmacology of Halogenated 未-Opioid-Selective [d-Ala2]Deltorphin II Peptide Analogues

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• 作者：Robyn Pescatore ; Gina F. Marrone ; Seth Sedberry ; Daniel Vinton ; Netanel Finkelstein ; Yitzchak E. Katlowitz ; Gavril W. Pasternak ; Krista R. Wilson ; Susruta Majumdar
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：905-910
• 全文大小：251K
• ISSN：1948-7193

文摘

Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are 未-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-Ala²]deltorphin II template, which is 未-selective in in vitro radioligand binding assays over the 渭- and 魏-opioid receptors. It is a full agonist in [³⁵S]GTP纬S functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective 未 receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the 未-opioid receptor. We have established a radioligand in which ¹²⁵I is incorporated into 3 (GATE3-8). The radioligand has a K_D of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the 未 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 Phe³. The peptides were characterized for binding affinity at the 渭-, 未-, and 魏-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 未-opioid receptor pharmacology.