Additional file 1: of Conditioned place preference training prevents hippocampal depotentiation in an orexin-dependent manner

Supplementary data. (DOC 848 kb

Total Synthesis of Hispidulin and the Structural Basis for Its Inhibition of Proto-oncogene Kinase Pim‑1

A new method is applied to synthesize hispidulin, a natural flavone with a broad spectrum of biological activities. Hispidulin exhibits inhibitory activity against the oncogenic protein kinase Pim-1. Crystallographic analysis of Pim-1 bound to hispidulin reveals a binding mode distinct from that of quercetin, suggesting that the binding potency of flavonoids is determined by their hydrogen-bonding interactions with the hinge region of the kinase. Overall, this work may facilitate construction of a library of hispidulin-derived compounds for investigating the structure–activity relationship of flavone-based Pim-1 inhibitors

Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ‑Aminobutyric Acid Type A Receptor (GABA_AR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability

Recent reports indicate that α6β2/3γ2 GABA_AR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABA_AR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA_AR α6 subtype was retained. <b>8b</b> was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABA_ARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABA_ARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA_AR α6β2/3γ2 subtypes