Synthesis of σ receptor ligands with unsymmetrical spiro connection of the piperidine moiety

Abstract

The symmetrically connected spiro[[2]benzopyran-1,4′-piperidines] 1 are highly potent and selective σ 1 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 CeCl 3 ( 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 σ 1 and σ 2 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 σ 1 receptor affinities, whereas the selectivity over σ 2 and NMDA receptors was retained. A stereoselective interaction of the σ 1 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 σ 1 receptor protein.