Synthesis of bridged piperazines with sigma receptor affinity.
Bridged piperazines 4 were designed as conformationally restricted piperazine sigma receptor ligands. The chiral pool synthesis started from (S)-glutamate, which was transformed in five reaction steps into the piperazinediones 5 bearing a propionic acid ester side chain. A two-step Dieckmann analogous cyclization provided the bicyclic ketones 7 as key intermediates. The alcohols 8 were prepared by LiAlH4 reduction of the ketones 7. NaBH4 reduction, Williamson ether synthesis and LiAlH4 reduction led to the methyl and benzyl ethers 12 and 13. High sigma1 affinity is attained when one large substituent is introduced either at N-8 or O-2. The most potent sigma1 ligand in this series of compounds is the methyl ether 12b with the N-butyl substituent (K(i)=13.2 nM, selectivity sigma2:sigma1 = 16). Moreover, the N-methyl derivatives 13a (sigma2: K(i)=30.4 nM) and 12a (sigma2 preference) represent promising starting points for the development of potent and selective sigma2 ligands.
Weigl
Manuela
M
Institut für Pharmazeutische und Medizinische Chemie, Hittorfstrasse 58-62, 48149 Münster, Germany.
Wünsch
Bernhard
B
D003432:Cross-Linking Reagents / Q000737:chemistry*; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D017480:Receptors, sigma / Q000378:metabolism*
D003432:Cross-Linking Reagents; D010879:Piperazines; D017480:Receptors, sigma; D000077489:Piperazine