Synthesis of sigma receptor ligands with unsymmetrical spiro connection of the piperidine moiety.
The symmetrically connected spiro[[2]benzopyran-1,4'-piperidines] 1 are highly potent and selective sigma(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 sigma(1) and sigma(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 sigma(1) receptor affinities, whereas the selectivity over sigma(2) and NMDA receptors was retained. A stereoselective interaction of the sigma(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 sigma(1) receptor protein.
Jasper
Annemarie
A
Institut für Pharmazeutische und Medizinische Chemie, Hittorfstrasse 58-62, 48145 Münster, Germany.
Schepmann
Dirk
D
Lehmkuhl
Kirstin
K
Vela
Jose Miguel
JM
Buschmann
Helmut
H
Holenz
Jörg
J
Wünsch
Bernhard
B
D000818:Animals; D006168:Guinea Pigs; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010880:Piperidines; D017480:Receptors, sigma; D013141:Spiro Compounds; C032727:piperidine