Identification, structure–activity relationships and molecular modeling of potent triamine and piperazine opioid ligands Original Research Article

Opioid receptors are important targets for pain management. Here, we report the synthesis and biological evaluation of three positional scanning combinatorial libraries, consisting of linear triamines and piperazines. A highly potent (14 nM) and selective (IC50(μ)/IC50(κ) = 71; IC50(δ)/IC50(κ) = 714) triamine for the κ-opioid receptor was found. In addition, non-selective μ–κ binders were obtained, with binding affinities of 54 nM and 22 nM for μ- and κ-opioid receptors, respectively. Structure–activity relationships of each subset are described. 3D molecular alignments based on shape similarity to internal and external query molecules were carried out. For the combinatorial chemistry dataset studied here a 1.3 similarity cut-off value was observed to be efficient in the rocs-based alignment method. Interactions from the overlays analyzed in the binding sites of homology models of the receptors revealed specific substitution patterns for enhancing binding affinity in the piperazine series. Pharmacophore modeling of the compounds found from the three combinatorial libraries was also performed. The pharmacophore model indicated that the important feature for receptor binding activity with the μ-receptor was the presence of at least one hydrogen bond acceptor and one aromatic hydrophobic group. Whereas for the κ-receptor two binding modes emerged with one set of compounds employing the hydrogen bond acceptor and aromatic hydrophobic group, and a second set possibly via interactions with the receptor by hydrophobic and ionic salt-bridges.