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.

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ1 receptor affinity

“…Membrane preparation from guinea pig brains (σ 1 receptor) and rat liver (σ 2 receptor) were employed as receptor material. [ 3 H]‐(+)‐Pentazocine and [ 3 H]di‐ o ‐tolylguanidine served as radioactive competitors in the σ 1 and σ 2 assay, respectively …”

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

“…[29][30][31] Up to a test compound concentration of 10 lM the diastereomeric propellanamines syn-3 and anti-3 did not interact with r 1 and r 2 receptors.…”

Oxa-Pictet–Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure

“…Since di-o-tolylguanidine also interacts with  1 receptors, an excess of (+)-pentazocine was added to mask the  1 receptors. [45][46][47] The affinity data of the tested 2-benzopyrans are summarized in Table 1. * For low-affinity compounds only the inhibition of the radioligand binding (in %) at a test compound concentration of 1 µM is given.…”