Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy 渭 Opioid Receptor (MOR) Agonist/未 Opioid Receptor (DOR) Antagonist Ligands

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• 作者：Henry I. Mosberg ; Larisa Yeomans ; Aubrie A. Harland ; Aaron M. Bender ; Katarzyna Sobczyk-Kojiro ; Jessica P. Anand ; Mary J. Clark ; Emily M. Jutkiewicz ; John R. Traynor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：2139-2149
• 全文大小：353K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a 渭 opioid receptor (MOR) agonist, 未 opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood鈥揵rain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.