title: Synthesis, σ receptor affinity, and pharmacological evaluation of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-benzazepines.
abstract: In accordance with a novel strategy for generating the 2-benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2-benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-benzazepine (19 b) and (±)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität, Münster, Corrensstraße 48, 48149 Münster (Germany).
authors.forename: Peer
authors.initials: P
authors.lastname: Hasebein
authors.forename: Bastian
authors.initials: B
authors.lastname: Frehland
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D001552:Benzazepines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma
keywords: antidepressant activity; benzazepines; neuropathic pain; receptors; structure-activity relationships