Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties.

A series of novel σ1 receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents. 1-Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per-residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine-N-atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non-small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1-Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.

Pharmacological characterization of high-affinity σ1 receptor ligands with spirocyclic thienopyran and thienofuran scaffold.

OBJECTIVES: In this study, the pharmacological properties of six spirocyclic piperidines 1-6 showing very high σ1 receptor affinity (Ki  = 0.2-16 nm) 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 σ1 receptor. The increased Ca2+ influx mediated by 2 and the analgesic activity of 1, 4, 5 and 6 confirm σ1 receptor antagonistic activity. Inhibition of human tumour cell growth further supports the σ1 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 σ1 antagonists represent promising antitumour agents.

Systematic variation of the benzoylhydrazine moiety of the GluN2A selective NMDA receptor antagonist TCN-201.

GluN2A containing N-methyl-D-aspartate receptors (NMDARs) are important ion channels in the central nervous system and highly involved in several different neurophysiological but also neuropathophysiological processes. However, current understanding of the contribution of GluN2A containing NMDARs in these processes is incomplete. Therefore, highly selective compounds are required to further investigate these ion channels. In 2010, TCN-201 (2), one of the first selective negative allosteric modulators was reported. While the binding site of 2 and the influence of the substitution pattern of the benzenesulfonamide part has been reported recently, detailed structure-activity-relationships of the diacylhydrazine part and the linked phenyl moiety are still missing. In order to examine the critical interactions between these moieties and the binding site, several TCN-201 analogs with modified diacylhydrazine part were synthesized. The negative allosteric effect was recorded by two-electrode voltage clamp (TEVC) experiments using GluN1a/GluN2A expressing Xenopus laevis oocytes. Our data led to the conclusion, that the terminal phenyl moiety is involved in a cation-π-interaction with the guanidinium moiety of Arg755 of the GluN1a subunit, which plays a crucial role for high activity. Additionally, structure optimization by replacing the phenyl moiety with a thiophen-2-yl (10c), indol-2-yl (10g) or indol-3-yl (10h) moiety significantly increased the activity of 2 by the factor 2.5. At a test compound concentration of 200 nM, the negative allosteric effect of the most potent ligands 10c, 10h and 17 was significantly influenced by the glycine concentration. Although glycine dependency is higher than those of the lead compound 4, 10c and 17 showed significantly higher negative allosteric effects than 4 at glycine concentrations from 1 µM up to 10 µM. The potent GluN2A-NMDA receptor inhibitors 10c, 10h and 17 did not influence the ion current of GluN2B-NMDA receptors.