Improving Metabolic Stability by Glycosylation: Bifunctional Peptide Derivatives That Are Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

详细信息    查看全文

• 作者：Takashi Yamamoto ; Padma Nair ; Neil E. Jacobsen ; Josef Vagner ; Vinod Kulkarni ; Peg Davis ; Shou-wu Ma ; Edita Navratilova ; Henry I. Yamamura ; Todd W. Vanderah ; Frank Porreca ; Josephine Lai ; Victor J. Hrub
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5164-5175
• 全文大小：1025K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

In order to obtain a metabolically more stable analgesic peptide derivative, O-β-glycosylated serine (Ser(Glc)) was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3′,5′-Bzl(CF₃)₂) which was a previously reported bifunctional compound with δ/μ opioid agonist and neurokinin-1 receptor antagonist activities and with a half-life of 4.8 h in rat plasma. Incorporation of Ser(Glc) into various positions of TY027 gave analogues with variable bioactivities. Analogue 6 (Tyr-d-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3′,5′-Bzl(CF₃)₂) was found to have effective bifunctional activities with a well-defined conformation with two β-turns based on the NMR conformational analysis in the presence of DPC micelles. In addition, 6 showed significant improvement in its metabolic stability (70 ± 9% of 6 was intact after 24 h incubation in rat plasma). This improved metabolic stability, along with its effective and δ selective bifunctional activities, suggests that 6 could be an interesting research tool and possibly a promising candidate as a novel analgesic drug.