Cannabidiol (CBD), the main nonpsychoactive constituent of Cannabis sativa, has shown a wide range of therapeutically promising pharmacological effects either as a sole drug or in combination with other drugs in adjunctive therapy. However, the targets involved in the therapeutic effects of CBD appear to be elusive. Furthermore, scarce information is available on the biological activity of its human metabolites which, when formed in pharmacologically relevant concentration, might contribute to or even account for the observed therapeutic effects. The present overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD in humans, reviews studies on the biological activity of CBD metabolites either in vitro or in vivo, and discusses relevant drug–drug interactions. To facilitate further research in the area, the reported syntheses of CBD metabolites are also catalogued.

Based on analysis of pheromone gland extracts, highly attractive new baits have been developed for three click beetle pests. That for Agriotes brevis is a mixture of geranyl butanoate and (E,E)-farnesyl butanoate, and that for A rufipalpis and A sordidus contains geranyl hexanoate alone. From known data from species populating Russia, optimized bait compositions for species in Central and Western Europe were developed as follows: geranyl octanoate + geranyl butanoate for A lineatus, geranyl isovalerate for A litigiosus, geranyl hexanoate + geranyl octanoate for A obscurus, geranyl butanoate alone for A sputator and (E,E)-farnesyl acetate alone for A ustulatus. Although slight differences were found in gland contents with A litigiosus var laichartingi and fenotypus typicus, nevertheless there were no differences in response to the optimum bait. There were no differences in pheromone composition or response to the optimized bait between the two morphological forms ('black' and 'red') of A ustulatus. As a result of these studies, highly effective pheromone baits are now available for monitoring and population reduction in all important pest click beetle species in Central and Western Europe.

As a continuation of our project aimed at the search for new and safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas' disease), several drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (4) were designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. This thiocyanate derivative was previously shown to be an effective and potent agent against T. cruzi proliferation. Several drugs possessing thiocyanate groups proved to be effective growth inhibitors of T. cruzi growth. Among the designed compounds, it is important to point out the extremely potent activity shown by 11, 23, 38, 53, 90, 99, and 117 against the epimastigote forms of the parasite. All of them exhibited IC(50) values in the low micromolar range, and these values were comparable with those presented by our lead drug 4 and ketokonazole, a well-known antiparasitic agent. The activity displayed by the nitrogen-containing derivative 90 was very promising with IC(50) values of 3.3 microM. Several other thiocyanate derivatives also proved to be very potent inhibitors of the multiplication of T. cruzi epimastigotes, such as compounds 28, 33, 43, 48, 56, 61, 66, 71, 76, and 124. Compound 43 resulted in being a promising drug because it was also very effective against amastigotes, the clinically more relevant form of the parasite. This compound was 3-fold more potent than 4, while 11 showed nearly the same activity as our lead drug against intracellular T. cruzi. It was very surprising that the experimental juvenoid 124, although fairly devoid of activity against epimastigotes, was very effective against intracellular amastigotes growing in myoblasts. The rest of the designed compounds showed a broad degree of inhibitory action, from moderately active drugs to drugs almost devoid of antiparasitic activity. Compound 43 is an interesting example of an effective antichagasic agent that presents excellent prospectives not only as a lead drug but also to be used for further in vivo studies.

Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective μ opioid receptor agonists possessing morphine-like pharmaco­toxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which “brorphine” made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

No abstract

No abstract

Biosynthesis and metabolism of juvenile hormone (JH) III in vivo and in vitro were studied in female Aedes aegypti (L.). [12-3H]Methyl farnesoate was used to follow the synthesis and [12-3H]-(10R)-JH III to study metabolism. The rate of biosynthesis of [12-3H]JH III in vivo after adult eclosion increased from 9 fmol/h per female at 1 h to 22 fmol/h per female at day 6. The rate of biosynthesis by exposed corpora allata (CA) in vitro was 23 fmol/h per CA during the 1st d after adult eclosion, then dropped to 4.8 fmol/h per CA on day 3, then increased again to a constant level of synthesis (12 fmol/h per CA) at days 4-6. Immediately after blood feeding, the rate of synthesis of [12-3H]JH III in vivo and in vitro increased to 27 fmol/h per female and to 23 fmol/h per CA, respectively. The rate of synthesis then decreased in vivo to 12 fmol/h per female at 4 h and in vitro to 6 fmol/h per CA 10 h after the blood meal. After this decrease, the rate of synthesis of [12-3H]JH III increased again reaching a peak of 25 fmol/h per female at 48-96 h in vivo and 12 fmol/h per CA at 72 h in vitro. These results indicated that the CA of sugar-fed and blood-fed female A. aegypti synthesized JH III in vivo and in vitro from [12-3H]methyl farnesoate. When [12-3H]-(10R)-JH III metabolism was followed in vivo in female A. aegypti, the ratio between JH III diol acid:JH III acid:JH III diol was 17:4:1, indicating that JH III was first hydrolyzed by JH III esterase to the acid form, then hydrated to the diol acid by JH III epoxide hydrase. Females treated with [12-3H]JH III acid converted 46% of the JH III acid in 60 min to the diol acid. These results indicated that the enzyme epoxide hydrase acted on JH III acid 17 times faster than JH III.

No abstract