piperidines and ebselen

Deficits in impulse control feature in many psychiatric conditions including bipolar disorder, suicidality and addictions. Lithium lowers impulsivity in clinical populations and decreases pathological gambling in experimental medicine studies, but suffers from adverse effects, poor compliance and a low therapeutic index.. Recently we identified that the neuroprotective agent ebselen, which is reportedly safe in humans, inhibited inositol monophosphatase (IMPase), a candidate lithium mechanism. Ebselen also reduced 5-HT receptor (5-HT. Ebselen was tested in two models of impulsivity with human analogues: the five-choice serial reaction time task (5-CSRTT) and rodent gambling task (rGT). The main outcome measures were premature responses (5-CSRTT and rGT) and choice behaviour (rGT), which model motor impulsivity and choice impulsivity, respectively.. At doses that decreased 5-HT. These findings suggest that ebselen preferentially reduces motor impulsivity over choice impulsivity, and that inhibition of 5-HT

Topics: Animals; Azoles; Choice Behavior; Cocaine; Fluorobenzenes; Impulsive Behavior; Isoindoles; Male; Models, Animal; Neuroprotective Agents; Organoselenium Compounds; Piperidines; Rats; Reaction Time

Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA.. DHEA and NALA were found to effectively inhibit HNSCC cell proliferation. These anti-proliferative effects seemed to be mediated in a cannabinoid receptor-independent manner, since the antagonist of cannabinoid receptor-1 (CB1) and vanilloid receptor-1 (VR1), two endocannabinoid receptors, did not reverse the ability of DHEA and NALA to induce cell death. Instead, we observed an increase in reactive oxygen species (ROS) production and a decrease of phosphorylated Akt as a result of DHEA and NALA treatment. Antioxidants efficiently reversed the inhibition of cell proliferation and the decrease of phosphorylated Akt induced by DHEA and NALA; inhibition of 5-lipoxygenase (5-LO), which is expected to be involved in DHEA- and NALA-degradation pathway, also partially blocked the ability of DHEA and NALA to inhibit cell proliferation and phosphorylated Akt. Interestingly, ROS production as a result of DHEA and NALA treatment was decreased by inhibition of 5-LO.. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.

Topics: Alanine; Antineoplastic Agents; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Azoles; Benzoquinones; Carcinogenesis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Endocannabinoids; Head and Neck Neoplasms; Humans; Hydroxyurea; Isoindoles; Lipoxygenase Inhibitors; Organoselenium Compounds; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Pyrazoles; Reactive Oxygen Species; Receptor, Cannabinoid, CB1; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TRPV Cation Channels

A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Azoles; Butyrylcholinesterase; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Donepezil; Electrophorus; Glutathione Peroxidase; Humans; Indans; Isoindoles; Kinetics; Ligands; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Organoselenium Compounds; Peptide Fragments; Peroxynitrous Acid; Piperidines; Protein Multimerization; Protein Structure, Secondary; Thioredoxin-Disulfide Reductase; Toxicity Tests, Acute