Azologization of serotonin 5-HT3 receptor antagonists.

Karin Rustler,Galyna Maleeva,Burkhard König,Piotr Bregestovski

doi:10.3762/bjoc.15.74

Abstract

The serotonin 5-hydroxytryptamine 3 receptor (5-HT3R) plays a unique role within the seven classes of the serotonin receptor family, as it represents the only ionotropic receptor, while the other six members are G protein-coupled receptors (GPCRs). The 5-HT3 receptor is related to chemo-/radiotherapy provoked emesis and dysfunction leads to neurodevelopmental disorders and psychopathologies. Since the development of the first serotonin receptor antagonist in the early 1990s, the range of highly selective and potent drugs expanded based on various chemical structures. Nevertheless, on-off-targeting of a pharmacophore’s activity with high spatiotemporal resolution as provided by photopharmacology remains an unsolved challenge bearing additionally the opportunity for detailed receptor examination. In the presented work, we summarize the synthesis, photochromic properties and in vitro characterization of azobenzene-based photochromic derivatives of published 5-HT3R antagonists. Despite reported proof of principle of direct azologization, only one of the investigated derivatives showed antagonistic activity lacking isomer specificity.

Highlights

Serotonin operates via seven classes of 5-HT receptors of which six are G protein-coupled receptors (GPCRs) and only one, the 5-hydroxytryptamine receptor (5-HT3R), is a ligand-gated cation channel [5,6,17]
Referring to this work performed by the groups of DiMauro [60] and Jensen [61], we envisioned that the replacement of the thioether or amide bond (Scheme 1) by an azo bridge would result in highly active photochromic serotonin 5-HT receptor (5-HTR) antagonists controllable by irradiation with light
Nitrosoquinoxaline 3 was synthesized in a two-step procedure starting from 2-chloroquinoxaline (1), which was transformed into its oxime 2 using hydroxylammonium chloride [64]

Summary

Introduction

Serotonin operates via seven classes of 5-HT receptors of which six are G protein-coupled receptors (GPCRs) and only one, the 5-HT3R, is a ligand-gated cation channel [5,6,17]. The primary design of our photochromic derivatives is based on the direct “azologization” [59] of reported non-photochromic antagonists [60,61] via replacement of the benzenering connecting amide bond and thioether, respectively, by an azo bridge. Referring to this work performed by the groups of DiMauro [60] and Jensen [61], we envisioned that the replacement of the thioether or amide bond (Scheme 1) by an azo bridge would result in highly active photochromic serotonin 5-HTR antagonists controllable by irradiation with light.

Results

Conclusion