Efficient modulation of of γ-aminobutyric acid type A (GABAA) receptors by piperine derivatives

[Image: see text] Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABA(A)R). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABA(A)R by means of a two-microelectrode voltage-clamp technique. GABA(A)R were expressed in Xenopus laevis oocytes. Structure–activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABA(A)R. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABA(A) (maximal GABA-induced chloride current modulation (I(GABA-max) = 1673% ± 146%, EC(50) = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC(50) = 13.8 ± 1.8 μM, I(GABA-max) = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABA(A)R modulators

Influence of Different Polymer Belts on Lipid Properties in Nanodiscs Characterized by CW EPR Spectroscopy

Polymeric DMPC-nanodiscs from three polymers are viable membrane models. The polymers change water penetration and lipid rotational mobility within DMPC vilayers. SMA and SMA-SB have a stronger effect on lipid order than DIBMA.<br /

Molecular-Level Interactions of Nanodisc-Forming Copolymers Dissected by EPR Spectroscopy

In this study, we focus on analyzing the non-covalent interaction patterns between three lipid-nanodisc-forming polymers and nitroxide radicals which are used as small organic tracer molecules. Besides the negatively charged polymers DIBMA and SMA(2:1), we characterize the solvation behavior of a new zwitterionic styrene/maleic amide sulfobetaine copolymer named SMA-SB. The used nitroxide spin probes vary in their respective chemical structure, allowing the report of different local micropolarities and nanoscopic regions by recording temperature-dependent continuous-wave electron paramagnetic resonance (CW EPR) spectra. In combination with dynamic light scattering (DLS) and electrophoretic light scattering (ELS) experiments, we are able to provide a nanoscopic interpretation of the dominant interaction patterns between the polymer and the chosen guest molecule

Controlling interface anisotropy in CoFeB/MgO/HfO2 using dusting layers and magneto-ionic gating

International audienceIn this work, we present the magneto-ionic response to ionic liquid gating in Ta/CoFeB/MgO/HfO2 stacks, where heavy metal dusting layers of Ta, W, and Pt are inserted at the Ta/CoFeB and CoFeB/MgO interfaces. Dusting layers of W inserted at the Ta/CoFeB interface increase perpendicular magnetic anisotropy (PMA) by more than 50%, while no significant changes are seen for Pt. In these samples, gating cannot break the PMA seeded at the CoFeB/MgO interface, only relatively small changes in the coercivity can be induced, about 20% for Ta and Pt and 6% for W. At the CoFeB/MgO interface, a significant quenching of the magnetization is seen when W and Ta dusting layers are inserted, which remains unchanged after gating, suggesting a critical deterioration of the CoFeB. In contrast, Pt dusting layers result in an in-plane anisotropy that can be reversibly converted to PMA through magneto-ionic gating while preserving the polycrystalline structure of the MgO layer. This shows that dusting layers can be effectively used not only to engineer magnetic properties in multilayers but also to strongly modify their magneto-ionic performance