Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives

详细信息    查看全文

• 作者：Srinivas Deekonda^a ; Lauren Wugalter^a ; David Rankin^b ; Tally M. Largent-Milnes^b ; Peg Davis^b ; Yue Wang^b ; Neemah M. Bassirirad^b ; Josephine Lai^b ; Vinod Kulkarni^a ; Todd W. Vanderah^b ; Frank Porreca^b ; Victor J. Hruby^a ; ^{hruby@email.arizona.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ACN ; Acetonitrile ; Boc ; tert-butyloxycarbonyl ; CHO ; Chinese hamster ovary ; DCM ; Dichloromethane ; DIPEA ; N ; N-Diisopropylethylamine ; DALEA ; [D-Ala2 ; Leu5] enkephalin amide ; DAMGO ; [D-Ala2 ; NMePhe4 ; Gly5-ol]enkephalin ; Dmt ; 2 ; 6-dimethyltyrosine ; DPDPE ; c[D-Pen2 ; DPen5]enkephalin ; GPI ; guinea pig isolated ileum ; HBTU ; N ; N ; N&prime ; N&prime ; -Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate ; HATU ; 1-[Bis(dimethylamino)methylene]-1H-1 ; 2 ; 3-triazolo[4 ; 5-b]pyridinium3-oxid hexafluorophosphate
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 October 2015
• 年：2015
• 卷：25
• 期：20
• 页码：4683-4688
• 全文大小：608 K

文摘

We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at 渭 and 未 opioid receptors. They exhibit very good affinities at 渭 and 未 opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at 渭 and 未 opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.