Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands

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• 作者：Srinivas Deekonda^a ; Lauren Wugalter^a ; Vinod Kulkarni^a ; David Rankin^b ; Tally M. Largent-Milnes^b ; Peg Davis^b ; Neemah M. Bassirirad^b ; Josephine Lai^b ; 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 ; BH3-SMe2 ; Borane dimethylsulfide ; CHO ; Chinese hamster ovary ; DALEA ; [D-Ala2 ; Leu5] enkephalin amide ; DCM ; dichloromethane ; DCE ; dichloroethane ; DOR ; delta opioid receptor ; DHP ; dihydropyran ; DIPEA ; N ; N-diisopropylethylamine ; DAMGO ; [D-Ala2 ; NMePhe4 ; Gly5-ol]enkephalin ; DPDPE ; c[D-Pen2 ; DPen5]enkephalin ; Dmt ; 2 ; 6-dimethyltyrosine ; GPI ; guinea pig isolated ileum ; GPCR ; G protein-coupled receptor ; HRMS ; high resolution mass spectrometry ; HCl ; hydrochlori
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：15 September 2015
• 年：2015
• 卷：23
• 期：18
• 页码：6185-6194
• 全文大小：693 K

文摘

A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on 渭 and 未 opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the 渭 and 未 opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the 渭 opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the 渭 opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.