Synthesis and characterization of N N-dialkyl and N-alkyl-N-aralkyl fenpropimorph-derived compounds as high affinity ligands for sigma receptors

摘要

The sigma-1 receptor is a unique non-opioid, non-PCP binding site that has been implicated in many different pathophysiological conditions including psychosis, drug addiction, retinal degeneration and cancer. Based on the structure of fenpropimorph, a high affinity (Ki= 0.005nM) sigma-1 receptor ligand and strong inhibitor of the yeast sterol isomerase (ERG2), we previously deduced a basic sigma-1 receptor pharmacophore or chemical backbone composed of a phenyl ring attached to a di-substituted nitrogen atom via an alkyl chain . Here, we report the design and synthesis of various N, N-dialkyl or N-alkyl-N-aralkyl derivatives based on this pharmacophore as well as their binding affinities to the sigma-1 receptor. We introduce three high affinity sigma-1 receptor compounds, N, N-Dibutyl-3-(4- fluorophenyl)propylamine (>9), N.N-Dibutyl-3-(4-nitrophenyl)propylamine >(3), and NPropyl- N’-4-aminophenylethyl-3-(4-nitrophenyl)propylamine (>20) with Ki values of 17.7 nM, 0.36 nM, and 6 nM, respectively. In addition to sigma receptor affinity, we show through cytotoxicity assays that growth inhibition of various tumor cell lines occurs with our high affinity N, N-dialkyl or N-alkyl-N-aralkyl derivatives.