Design synthesis and structure–activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd. W.; Porecca, Frank; Hruby, Victor J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 2(2016)
• Page Start: 85
• Page End: 91
• Publication Date: 2016-01-15
• Subjects: 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 [d-Ala2, Leu5]enkephalin amide -- hDOR human δ opioid receptor -- DPDPE c[D-Pen2, DPen5]enkephalin -- dAMGO [d-Ala2, NMePhe4, Gly5-ol]enkephalin -- Dmt 2, 6-dimethyltyrosine -- Tyr tyrosine -- GPI guinea pig isolated ileum -- LMMP longitudinal muscle with myenteric plexus -- rMOR rat μ opioid receptor -- MVD mouse vas deferens -- RP-HPLC reverse phase high performance liquid chromatography -- HRMS high resolution mass spectrometry -- SAR structure–activity relationship -- TFA trifluoroacetic acid -- TLC thin layer chromatography; Opioids -- Opioid receptors -- Pain -- N-Phenyl-N-(piperidin-2-yl)propionamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.11.030
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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, ligands19 and20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand19 showed potent agonist activities 75 ± 21 nM, and 190 ± 42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue20 showed good agonist activities in MVD assays 170 ± 42 nM, in contrast to its binding affinity results.