Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5-Phenylsulfanyl- and 5-Benzyl-Substituted Tetrahydro-2-benzazepines

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 sigma(1) 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 (19b) and (+/-)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (19m), show high selectivity over more than 50 other relevant targets, including the sigma(2) subtype and various binding sites of the N-methyl-d-aspartate (NMDA) receptor. In the Irwin screen, 19b and 19m showed clean profiles without inducing considerable side effects. Compounds 19b and 19m did not reveal significant analgesic and cognition-enhancing activity. Compound 19m did not have any antidepressant-like effects in mice.