Congratulations to Dr. Baselt for the publication of his 10th edition and the expansion of his classic toxicology text to cover over 1,500 medications and chemicals. This enduring work provides a c...

Disposition of Toxic Drugs and Chemicals in Man

https://escholarship.org/content/qt8xh0s7nf/qt8xh0s7nf.pdf?t=oyg19p

Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review

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Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review - eScholarship

A review: Fentanyl and non-pharmaceutical fentanyls

Compounds containing a 1,1-diaryl motif are numerous, and compounds of this type have found use as catalysts and molecular building blocks, however, this review focusses solely on chiral compounds, wherein the two aromatic rings attached to a central carbon are not identical, and highlights their use and importance as drugs and biologically active molecules.

Chiral 1,1-diaryl compounds as important pharmacophores

AH-7921 is a structurally unique synthetic opioid analgesic that has recently entered the drug arena in Europe, the USA, and Japan. Although it was synthesized and patented in the mid-1970s, it was first identified in a seized sample purchased via the Internet in July 2012 and formally brought to the attention of the European Union early warning system in August 2012 by the United Kingdom. Several in vitro experiments and animal model studies established the morphine-like analgesic action of AH-7921 as a μ-opioid receptor agonist that has been found to be several times more potent than codeine and at least as potent as morphine. This novel psychoactive substance has already led to eight non-fatal intoxications and 16 deaths in Sweden, the United Kingdom, Norway, and the USA. Thus, AH-7921 is a current public health risk, and better international collaboration, effective legislation and continuous community alertness are needed to tackle this current growing problem. The aim of this review is to summarize the current knowledge about this drug concerning its chemistry, pharmacology, and toxicology, as well as its international legal status. The limited existing analytical methodologies for the determination of AH-7921 in biological samples are also presented. Published or reported AH-7921-related cases, fatalities, or intoxications, and self reports from drug users are reviewed.

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AH-7921: the list of new psychoactive opioids is expanded

Atherosclerosis is a multifactorial disease with several mechanisms participating in its manifestation. To address this disorder, we applied a strategy involving the design of a single chemical compound able to simultaneously modulate more than one target. We hereby present the development of novel benzoxazine and benzothiazine derivatives that significantly inhibit in vitro microsomal lipid peroxidation and LDL oxidation as well as squalene synthase activity (IC50 of 5–16 μM). Further, these compounds show antidyslipidemic and antioxidant properties in vivo, decreasing total cholesterol, LDL, triglyceride, and MDA levels of hyperlipidemic rats by 26–74%. Finally, by determination of their in vivo concentration (up to 24 h) in target tissues (blood/liver), it is shown that compounds reach their targets in the low micromolar range. The new compounds seem to be interesting multifunctional molecules for the development of a new pharmacophore for disease-modifying agents useful in the treatment of atheroscler...

Novel Benzoxazine and Benzothiazine Derivatives as Multifunctional Antihyperlipidemic Agents

Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors.Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

“Flakka” is the street name for the synthetic cathinone α-pyrrolidinopentiophenone (α-PVP). Although it was developed by Boehringer Ingelheim as a central nervous system stimulant and pressor agent in the 1960s, it entered in the drug arena at an accelerated rate during the last 4 years causing intoxications, fatal or not. α-PVP is abused in Europe, as well as in the United States and Japan, as a substituent of 3, 4-methylenedioxypyrovalerone, and recently scheduled by the United States Drug Enforcement Administration, possessing similar pharmacological action to that of the latter. It can be easily manufactured and purchased through the Internet or in retail shops and is usually sold as “bath salts”. The aim of this review is to summarize the current knowledge of this drug concerning its chemistry, synthesis, metabolism, pharmacology, and toxicology. “Flakka” related cases, published or reported, including fatalities or intoxications, as well as seizures are reviewed. The existing analytical methodologies for the determination of α-PVP in biological and postmortem samples are summarized, and its current legal status is reported.

α-PVP (“flakka”): a new synthetic cathinone invades the drug arena

In multi-target drug design (MTD) medicinal chemistry aims to integrate multiple pharmacophores into a singledrug molecule in order to make it active on several molecular biological mechanisms simultaneously. Given the fact thatmost diseases are multifactorial in nature, MTD is being pursued with increasing intensity, which has resulted in improvedoutcomes in disease models and several compounds have entered clinical trials. In a wide range of examples we illustratehow various functionalities have been combined within single structures and how this has affected their (pre)clinical outcome.This review describes the successful application of MTD for disorders such as neurodegenerative, cardiovascular,diabetes, metabolic and inflammatory diseases, especially focusing on the field of atherosclerosis where multi-targetstrategies are a promising alternative to the classical “one target-one drug” design approach.

Maria Katselou

Papers

AH-7921: the list of new psychoactive opioids is expanded

Novel Benzoxazine and Benzothiazine Derivatives as Multifunctional Antihyperlipidemic Agents

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

α-PVP (“flakka”): a new synthetic cathinone invades the drug arena

Multi-Target Drug Design Approaches for Multifactorial Diseases: From Neurodegenerative to Cardiovascular Applications