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

摘要

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 mu opioid receptor over the delta 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 mu 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. (C) 2015 Elsevier Ltd. All rights reserved.