3 research outputs found
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<sub>A</sub>R) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
Recent
reports indicate that α6β2/3γ2 GABA<sub>A</sub>R
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<sub>A</sub>R 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<sub>A</sub>R 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<sub>A</sub>Rs
and were functionally silent at diazepam sensitive α1β2/3γ2
GABA<sub>A</sub>Rs, 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<sub>A</sub>R α6β2/3γ2
subtypes