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7459450 
Journal Article 
Design, synthesis and receptor affinity of novel conformationally restricted σ ligands based on the [4.3.3]propellane scaffold 
Torres-Gã³Mez, H; Lehmkuhl, K; Schepmann, D; Wã¼Nsch, B 
2013 
Yes 
European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254 
Elsevier Masson SAS 
70 
78-87 
English 
A series of novel diastereoisomeric σ ligands 3 was designed, synthesized and pharmacologically evaluated. The highly rigid [4.3.3]propellane scaffold was used to fix the three dimensional orientation of the pharmacophoric moieties required for σ affinity. The syn,syn-configured aminocarbamate syn,syn-3a reveals the most promising σ1 affinity (K i = 77 nM) and selectivity over the σ2 subtype (21-fold). The σ2 affinity of all four diastereomers 3 was in the low micromolar range. Analysis of the distance between the hydrophobic regions (phenyl moieties) of the diastereomers 3 led to the longest range of distances (10.3-15.2 Å) for the most potent σ1 ligand syn,syn-3a, which is in good agreement with pharmacophore models. © 2013 Elsevier Masson SAS. All rights reserved. 
Conformational restriction; Pharmacophore models; Stereoselective reduction; [4.3.3]Propellane; σ Ligands; (anti 11 oxo[4.3.3] propellan 8 yl) n (2 methoxy 5 methylphenyl)carbamate; (syn 11 oxo[4.3.3]propellan 8 yl) n (2 methoxy 5 methylphenyl)carbamate; anti 11 hydroxy[4.3.3]propellan 8 one; hydrocarbon; syn 11 hydroxy[4.3.3]propellan 8 one; tetramethyl 8,11 dioxo[4.3.3]propellane 7,9,10,12 tetracarboxylate; unclassified drug; [(8 anti 11 anti) (11 benzylamino)[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 anti 11 anti) 11 hydroxy[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 anti 11 syn) 11 hydroxy[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 anti 11 syni) (11 benzylamino)[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 syn 11 anti) (11 benzylamino)[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 syn 11 anti) 11 hydroxy[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 syn 11 syn) (11 benzylamino)[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [(8 syn 11 syn) 11 hydroxy[4.3.3]propellan 8 yl] n (2 methoxy 5 methylphenyl)carbamate; [4.3.3]propellane 8,11 dione; animal tissue; article; binding affinity; binding assay; diastereoisomer; drug design; drug synthesis; molecular model; nonhuman; pharmacophore; protein determination; rat; receptor binding; Conformational restriction; Pharmacophore models; Stereoselective reduction; [4.3.3]Propellane; σ Ligands; Animals; Brain; Bridged Compounds; Dose-Response Relationship, Drug; Drug Design; Guinea Pigs; Ligands; Liver; Molecular Conformation; Rats; Receptors, sigma; Stereoisomerism; Structure-Activity Relationship