Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands

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• 作者：Srinivas Deekonda^a ; David Rankin^b ; Peg Davis^b ; Josephine Lai^b ; Todd. W. Vanderah^b ; Frank Porecca^b ; Victor J. Hruby^a ; ^{hruby@email.arizona.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GPCR ; G protein-coupled receptor ; MOR ; Mu opioid receptor ; DOR ; delta opioid receptor ; Boc ; tert-butyloxycarbonyl ; NaOtBu ; sodium tert-butoxide ; Et3N ; triethylamine ; HCl ; hydrochloric acid ; BH3-SMe2 ; borane dimethylsulfide ; DHP ; dihydropyran ; PPTS ; pyridinium p-toluenesulfonate ; Ph3P ; triphenylphosphine ; Na(OAc)3BH ; sodium triacetoxyborohydride ; DCE ; dichloroethane ; DIPEA ; N ; N-diisopropylethylamine ; ACN ; acetonitrile ; DCM ; dichloromethane ; rt ; room temperature ; CHO ; Chinese hamster ovary ; dALEA
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：24
• 期：2
• 页码：85-91
• 全文大小：560 K

文摘

Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850–4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75 ± 21 nM, and 190 ± 42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170 ± 42 nM, in contrast to its binding affinity results.