title: Synthesis and pharmacological evaluation of like- and unlike-configured tetrahydro-2-benzazepines with the α-substituted benzyl moiety in the 5-position.
abstract: A large set of tetrahydro-2-benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-benzazepines with various binding sites of the NMDA receptor were not observed.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany. wuensch@uni-muenster.de.
authors.forename: Peer
authors.initials: P
authors.lastname: Hasebein
authors.forename: Bastian
authors.initials: B
authors.lastname: Frehland
authors.forename: Kirstin
authors.initials: K
authors.lastname: Lehmkuhl
authors.forename: Roland
authors.initials: R
authors.lastname: Fröhlich
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D008968:Molecular Conformation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism
chemical_list: D001552:Benzazepines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma