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Different sensitivities of porcine coronary arteries and veins to BAY 60-2770, a soluble guanylate cyclase activator.
J Pharmacol Sci
January 2025
Department of Pathological and Molecular Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan.
Nitric oxide (NO)-donor drugs, which stimulate reduced form of soluble guanylate cyclase (sGC), have different efficacy to the arteries and veins. This study examined whether sGC activators, which activate oxidized/apo sGC, also have arteriovenous selectivity similar to that of NO-donor drugs. The mechanical responses of the isolated blood vessels were assessed using the organ chamber technique and protein expression was verified using western blotting.
View Article and Find Full Text PDFCYP3A4-Mediated Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor JNJ-54861911 Results in Redox-Neutral Addition of Glutathione via Catalysis by Glutathione S-Transferase α1, Identified as the Major Target Protein in Human Hepatocytes.
Chem Res Toxicol
January 2025
Translational Pharmacokinetics, Pharmacodynamics and Investigative Toxicology, Janssen Research & Development, LLC, 2340 Beerse, Belgium.
The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver injury (DILI). This paper describes our investigation of the metabolism of JNJ-54861911 to understand the potential contribution to the observed DILI. In human hepatocytes, JNJ-54861911 is metabolized by CYP450 3A4 to a reactive intermediate (RI), which undergoes glutathione (GSH) addition at C6 of the 2-amino-4-methyl-1,3-thiazin-4-yl moiety via glutathione S-transferase α1 (GSTA1) catalysis.
View Article and Find Full Text PDFSerotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-,-dimethyltryptamine Analogs in Mice.
ACS Chem Neurosci
December 2024
Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States.
5-methoxy-,-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its -alkyl, -allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT) and 1A receptors (5-HT), and 3) to examine the influence of 5-HT on 5-HT-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.
View Article and Find Full Text PDFPPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice.
Toxicol Appl Pharmacol
January 2025
Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address:
Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, N-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver.
View Article and Find Full Text PDFNear-Infrared Visualization of NAD(P)H Dynamics in Live Cells and Larvae Using a Coumarin-Based Pyridinium Fluorescent Probe.
ACS Appl Bio Mater
December 2024
Department of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States.
A near-infrared fluorescent probe, , was designed by substituting the carbonyl group of the coumarin dye's lactone with a 4-cyano-1-methylpyridinium methylene group and then attaching an electron-withdrawing NADH-sensing methylquinolinium acceptor via a vinyl bond linkage to the coumarin dye at the 4-position. The probe exhibits primary absorption maxima at 603, 428, and 361 nm, and fluoresces weakly at 703 nm. The addition of NAD(P)H results in a significant blue shift in the fluorescence peak from 703 to 670 nm, accompanied by a substantial increase in fluorescence intensity.
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