Synthesis and characterization of N,N-dialkyl and N-alkyl-N-aralkyl fenpropimorph-derived compounds as high affinity ligands for sigma receptors.
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 (K(i)=0.005 nM)(1) 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.(2) 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 K(i) 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.
Hajipour
Abdol R
AR
Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Fontanilla
Dominique
D
Chu
Uyen B
UB
Arbabian
Marty
M
Ruoho
Arnold E
AE
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097605:Sigma-1 Receptor
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D008024:Ligands; D009025:Morpholines; D011437:Propylamines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C552768:N,N-dibutyl-3-(4-fluorophenyl)propylamine; C552767:N,N-dibutyl-3-(4-nitrophenyl)propylamine; C552769:N-propyl-N'-4-aminophenylethyl-3-(4-nitrophenyl)propylamine; C050435:fenpropimorph