Dataset Information

Identification of novel multitargeted PPAR?/?/? pan agonists by core hopping of rosiglitazone.

ABSTRACT: The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPAR?) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPAR? is the main cause of these side effects. Multitargeted PPAR?/?/? pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPAR?/?/? pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPAR?/?/? active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPAR?/?/? pan agonist for novel antidiabetic drug research.

SUBMITTER: Wang XJ

PROVIDER: S-EPMC4232041 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.

Wang Xue-Jiao XJ Zhang Jun J Wang Shu-Qing SQ Xu Wei-Ren WR Cheng Xian-Chao XC Wang Run-Ling RL

Drug design, development and therapy 20141107

The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hop ...[more]

PMID: 25422585

Similar Datasets

Project description:Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.

Dataset Information

Identification of novel multitargeted PPAR?/?/? pan agonists by core hopping of rosiglitazone.

Publications

Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets