Open AccessPharmacological characterization of high‐affinity σ 1 receptor ligands with spirocyclic thienopyran and thienofuran scaffold
Author(s) -
Schepmann Dirk,
Neue Christina,
Westphälinger Stefanie,
Müller Christoph,
Bracher Franz,
Lange Carsten,
Bednarski Patrick,
Almansa Carmen,
Friedland Kristina,
Räbiger Vivien,
Düfer Martina,
Wünsch Bernhard
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13196
Subject(s) - receptor , in vivo , chemistry , biochemistry , in vitro , cell culture , sterol , biosynthesis , pharmacology , enzyme , stereochemistry , biology , cholesterol , genetics , microbiology and biotechnology
Objectives In this study, the pharmacological properties of six spirocyclic piperidines 1 – 6 showing very high σ 1 receptor affinity ( K i = 0.2–16 n m ) were investigated. Methods In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tumour cell growth (cell lines A427, LCLC‐103H, 5637 and DAN‐G) was determined in different assays. The effect on the ergosterol and cholesterol biosynthesis was determined by GLC/MS analysis. Key findings Receptor binding studies demonstrated high selectivity for the σ 1 receptor. The increased Ca 2+ influx mediated by 2 and the analgesic activity of 1 , 4 , 5 and 6 confirm σ 1 receptor antagonistic activity. Inhibition of human tumour cell growth further supports the σ 1 antagonistic effects. Treatment of A427 tumour cells with 2 led to cell detachment and cell degradation. Whereas the ergosterol biosynthesis was not affected, the sterol C14‐reductase, a key enzyme in the cholesterol biosynthesis, was weakly inhibited. Conclusions Due to the high selectivity, off‐target effects are not expected. The antiallodynic activity underlines the clinical potential of the spirocyclic piperidines for the treatment of neuropathic pain. Due to the antiproliferative activity, the spirocyclic σ 1 antagonists represent promising antitumour agents.