کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1393230 | 1501195 | 2009 | 9 صفحه PDF | دانلود رایگان |
The symmetrically connected spiro[[2]benzopyran-1,4′-piperidines] 1 are highly potent and selective σ1 receptor ligands. Changing the position of the spirocyclic nitrogen atom led to the unsymmetrically connected spiro[[2]benzopyran-1,3′-piperidines] 2 with a reduced distance between the aromatic system and the basic nitrogen atom. The synthesis of 2 was performed by halogen–metal exchange at the aryl bromide 3 followed by addition to the piperidone 5 and intramolecular transacetalization. The yield of 2a was considerably improved by transmetallation of the aryllithium intermediate 4a with CeCl3 (4c). The cis and trans diastereomers cis-2 and trans-2 were separated and characterized by nuclear Overhauser effect. After removal of the benzyl group, the secondary amine 2b was alkylated with various alkyl and arylalkyl halides. The σ1 and σ2 receptor affinity of the spirocyclic piperidines 2 were determined with receptor binding studies. Compared with the spirocyclic piperidines 1, the unsymmetrically connected piperidines 2 show remarkably reduced σ1 receptor affinities, whereas the selectivity over σ2 and NMDA receptors was retained. A stereoselective interaction of the σ1 receptor protein with the cis- or trans-configured spirocyclic compounds 2 was not observed. It was shown that alkyl residues at the N-atom can replace the lipophilic N-arylalkyl groups and interact with the primary hydrophobic binding site of the σ1 receptor protein.
Figure optionsDownload as PowerPoint slide
Journal: European Journal of Medicinal Chemistry - Volume 44, Issue 11, November 2009, Pages 4306–4314