Design Synthesis and Structure–Activity Relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)Propionamide Derivatives as Opioid Ligands

Publication date: Available online 23 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Srinivas Deekond, David Rankin, Peg Davis, Josephine Lai, Todd. W. Vanderah, Frank Porecca, Victor J. Hruby
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 5^th 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 nM–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 5^th 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.

Graphical abstract

from #Medicine via ola Kala on Inoreader http://ift.tt/1I7G5se
via IFTTT