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Title of article :
Synthesis and characterization of N,N-dialkyl and N-alkyl-N-aralkyl fenpropimorph-derived compounds as high affinity ligands for sigma receptors Original Research Article
Author/Authors :
Abdol R. Hajipour، نويسنده , , Dominique Fontanilla، نويسنده , , Uyen B. Chu، نويسنده , , Marty Arbabian، نويسنده , , Arnold E. Ruoho، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2010
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Abstract :
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 = 0.005 nM) 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 N-propyl-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.
Keywords :
Cancer , Sigma receptor , Tumor cell lines , Fenpropimorphy
Journal title :
Bioorganic and Medicinal Chemistry
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