Zolpidem, a clinical hypnotic that affects electronic transfer, alters synaptic activity through potential GABA receptors in the nervous system without significant free radical generation

Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relationships (SAR) and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action

Novel, unifying mechanism for mescaline in the central nervous system: Electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships

A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting

Clinical physiology and mechanism of dizocilpine (MK-801): Electron transfer, radicals, redox metabolites and bioactivity

Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3′-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and anti-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties

Cardiovascular Diseases: Electron Transfer, Reactive Oxygen Species, Oxidative Stress, Toxicity, Antioxidants and Arrhythmia

Heart attacks comprise one of the main causes of death in the USA. A main adverse influence in the heart is arrhythmia involving disruption of cardiac electrical function. Another category of injury is necrosis. Mounting evidence implicates electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS) as important factors in cardiovascular diseases. In the generation of ROS, many in vivo enzymes are involved, in addition to exogenous agents. Less attention has been paid to ET functions as the source of ROS. Participation of OS is supported by beneficial effects of antioxidants, but not in all cases. It should be recognized that reaction mechanism is often multifacete

Multifaceted Approach to Resveratrol Bioactivity: Focus on Antioxidant Action, Cell Signaling and Safety

Resveratrol (RVT) is a naturally occurring trihydroxy stilbene that displays a wide spectrum of physiological activity. Its ability to behave therapeutically as a component of red wine has attracted wide attention. The phenol acts as a protective agent involving various body constituents. Most attention has been given to beneficial effects in insults involving cancer, aging, cardiovascular system, inflammation and the central nervous system. One of the principal modes of action appears to be as antioxidant. Other mechanistic pathways entail cell signaling, apoptosis and gene expression. There is an intriguing dichotomy in relation to pro-oxidant property. Also discussed are metabolism, receptor binding, rationale for safety and suggestions for future work. This is the first comprehensive review of RVT based on a broad, unifying mechanism

Asymmetric transfer hydrogenation of ketones in aqueous solution catalyzed by rhodium(III) complexes with C2-symmetric fluorene-ligands containing chiral (1R,2R)-cyclohexane-1,2-diamine

Two C2-symmetric bis(sulfonamide) ligands containing fluorene-chiral (1R,2R)-cyclohexane-1,2-diamine were complexed to RhIII(Cp*) and used as catalyst to reduce aromatic ketones. The corresponding chiral secondary alcohols were obtained in 87-100% ee and 85-99% yield, under asymmetric transfer hydrogenation (ATH) conditions using aqueous sodium formate as the hydride source. With acetophenone, 94% ee and 86-97% yield was achieved with substrate/catalyst (S/C) ratio of 10,000

Synthesis of some 2‐alkyl‐4‐quinolone and 2‐alkyl‐4‐methoxyquinoline alkaloids

Acid‐catalyzed condensation of a series of 3‐oxoalkanoic acid esters with aniline affords the corresponding 2‐alkyl‐4‐quinolones in good yield. Treatment of these compounds with methyl iodide affords 2‐alkyl‐4‐methoxyquinolines and 2‐alkyl‐N‐methylquinolones. Three of the compounds are naturally‐occurring alkaloids which are synthesized here for the first time. Copyright © 1981 Journal of Heterocyclic Chemistr

Unifying Mechanism for Eye Toxicity: Electron Transfer, Reactive Oxygen Species, Antioxidant Benefits, Cell Signaling and Cell Membranes

Eye toxicity comprises an important part in the category of insults to major organs. There is considerable literature comprising industrial chemicals, atmospheric pollutants, metals, pesticides, therapeutic drugs, abused drugs and household chemicals. The list includes both endogenous and exogenous materials. The various constituents of the eye are affected. This review provides extensive evidence for involvement of oxidative stress (OS) and electron transfer (ET) as a unifying theme. Successful application of the mechanistic approach is made to all of the main classes of toxicants, in addition to large numbers of miscellaneous types. We believe it is not coincidental that the vast majority of these substances incorporate ET functions(quinone, metal complex, ArNO2, or conjugated iminium) either per se or in metabolites, potentially giving rise to reactive oxygen species (ROS) by redox cycling. Some categories, e.g., peroxide and radiation, appear to generate ROS by non-ET routes. Beneficial effects of antioxidants are documented extensively, in addition to literature on cell signaling