Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review.

Since the early 2000s, there has been a turmoil on the global illicit cannabinoid market. Parallel to legislative changes in some jurisdictions regarding herbal cannabis, unregulated and cheap synthetic cannabinoids with astonishing structural diversity have emerged. Recently, semi-synthetic cannabinoids manufactured from hemp extracts by simple chemical transformations have also appeared as recreational drugs. The burst of these semi-synthetic cannabinoids into the market was sparked by legislative changes in the United States, where cultivation of industrial hemp restarted. By now, hemp-derived cannabidiol (CBD), initially a blockbuster product on its own, became a "precursor" to semi-synthetic cannabinoids such as hexahydrocannabinol (HHC), which appeared on the drug market in 2021. The synthesis and cannabimimetic activity of HHC were first reported eight decades ago in quest for the psychoactive principles of marijuana and hashish. Current large-scale manufacture of HHC is based on hemp-derived CBD extract, which is converted first by cyclization into a Δ8 /Δ9 -THC mixture, followed by catalytic hydrogenation to afford a mixture of (9R)-HHC and (9S)-HHC epimers. Preclinical studies indicate that (9R)-HHC has THC-like pharmacological properties. The animal metabolism of HHC is partially clarified. The human pharmacology including metabolism of HHC is yet to be investigated, and (immuno)analytical methods for the rapid detection of HHC or its metabolites in urine are lacking. Herein, the legal background for the revitalization of hemp cultivation, and available information on the chemistry, analysis, and pharmacology of HHC and related analogs, including HHC acetate (HHC-O) is reviewed.

Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB1 receptor ligand.

To investigate the possible interactions between kavalactone-based molecules and proteins of the endocannabinoid system and provide novel and synthetically accessible structural scaffolds for the design of cannabinoid receptor ligands sharing pharmacological properties with kavapyrones, a preliminary SAR analysis was performed on five commercially available natural kavalactones and nine kavalactone-analogues properly synthesized. These compounds were investigated for assessing their cannabinoid receptor binding affinity and capability of inhibiting the activity of the two major metabolic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Among the molecules tested, only yangonin exhibited affinity for the human recombinant CB1 receptor with a K(i)=0.72 µM and selectivity vs. the CB2 receptor (K(i)>10 µM). None of the compounds exhibited strong inhibitory effects on the two enzymes analyzed. The CB1 receptor affinity of yangonin suggests that the endocannabinoid system might contribute to the complex human psychopharmacology of the traditional kava drink and the anxiolytic preparations obtained from the kava plant.

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles.

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.

Species spectrum of flea beetles (Phyllotreta spp., Coleoptera, Chrysomelidae) attracted to allyl isothiocyanate-baited traps.

In field tests in Hungary, Slovenia and Bulgaria, in allyl isothiocyanate-baited traps significantly more beetles of Phyllotreta cruciferae, Ph. vittula, Ph. undulata, Ph. nigripes, Ph. nodicornis, Ph. balcanica, Ph. atra, Ph. procera, Ph. ochripes, Ph. diademata and Psylliodes chrysocephalus (Coleoptera, Chrysomelidae, Halticinae) were captured than in unbaited control traps. With the exception of Ph. cruciferae, this is the first report on significant field attraction by allyl isothiocyanate for these species. The species spectrum captured included six important agricultural pests. At all sites a great portion of the catch (ranging from ca 30 to 98%) was Ph. cruciferae, irrespective of the plant culture. The second most abundant species present at most sites was Ph. vittula. The present results are very promising from the point of view of applicability of allyl isothiocyanate in Europe as a bait in cabbage flea beetle traps for detection and monitoring.

Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy.

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.

Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi.

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.

Synthesis of (S)-3-(1-hydroxy-p-carboran-12-yl)alanine, a novel hydrophobic tyrosine-mimetic for peptides.

A new, p -carborane containing analog of tyrosine, 3-[1-hydroxy-1,12-dicarba-closo-dodecaboran (12)-12-yl]alanine, was prepared from protected 3-[1-hydroxy-1,12-dicarba-closo-dodecaboran (12)-12-yl]propionic acid in five steps using Oppolzer's sultam methodology for asymmetric hydroxyamination as the key step. The tyrosine mimetic can function as a hydrophobic surrogate for tyrosine residues in insect and mammalian neuropeptides to enhance the lipophilicity, and therefore, the cuticle and/or tissue permeability properties of mimetic analogs. As an amino acid, insertion of the mimic is not limited to the N-terminus but can replace a tyrosine residue at any position within a peptide sequence.

Identification of pheromones and optimization of bait composition for click beetle pests (Coleoptera: Elateridae) in Central and Western Europe.

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.

[Fragment-based drug design using stereoisomers. A case study of analogues of the phenol group in the Bioster database]. / Fragmentum-alapú hatóanyagtervezés a bioizosztéria alkalmazásával. Esettanulmány: a fenolcsoport analogonjai a Bioster adatbázisban.

This case study examined various structural features of the 55 bioisosteric fragments of the phenol group registered in version 2002.1 of the Bioster database. The size, calculated lipophilicity and H-bond donor or acceptor character of the fragments were found to vary on a fairly wide scale. In most cases, molecular modelling calculations indicated similarities in the electrostatic potential maps of the fragments.

Psychoactive natural products: overview of recent developments.

Natural psychoactive substances have fascinated the curious mind of shamans, artists, scholars and laymen since antiquity. During the twentieth century, the chemical composition of the most important psychoactive drugs, that is opium, cannabis, coca and "magic mushrooms", has been fully elucidated. The mode of action of the principal ingredients has also been deciphered at the molecular level. In the past two decades, the use of herbal drugs, such as kava, kratom and Salvia divinorum, began to spread beyond their traditional geographical and cultural boundaries. The aim of the present paper is to briefly summarize recent findings on the psychopharmacology of the most prominent psychoactive natural products. Current knowledge on a few lesser-known drugs, including bufotenine, glaucine, kava, betel, pituri, lettuce opium and kanna is also reviewed. In addition, selected cases of alleged natural (or semi-natural) products are also mentioned.

Drug laws and the 'derivative' problem.

The concept of a 'derivative' is used widely in chemistry, where its precise meaning depends on the circumstances. However, numerous examples of derivative also occur in domestic drugs legislation, some of which stem from the 1961 United Nations Single Convention on Narcotic Drugs. There is a commonly held view that only 'first-order' derivatives should be considered: substances that can be created from a parent structure in a single chemical reaction. In other words, 'derivatives of derivatives' are excluded. However, some substances related to ecgonine (e.g. 2-carbomethoxytropinone) are clearly convertible to cocaine, even though this may require more than one reaction step. It follows that 2-carbomethoxytropinone is a controlled drug, a situation that most chemists would regard as perverse. A more extreme example of the complexity of 'derivative' is shown by the conversion of thebaine to buprenorphine. Even though this requires six or more stages, the US Drug Enforcement Administration successfully argued in a 1986 case that for the purposes of the Controlled Substances Act, the number of steps required was irrelevant; buprenorphine was a derivative of thebaine. Because the term derivative is rarely defined in statutes, the legal status of some substances, such as 2-bromo-LSD, is uncertain. Although a number of definitions of derivative can be found in the chemical literature, no single definition is adequate to describe all situations where it occurs in legislation. Unless qualified, it is suggested that the term derivative should be avoided in any future legislation.

Identification of sex pheromone composition of click beetle Agriotes brevis candeze.

Geranyl butyrate (GB) and (E, E)-farnesyl butyrate (FB) were identified in the pheromone gland extract of females of the click beetle, Agriotes brevis (Candeze) (Coleoptera: Elateridae) as the major sex pheromone components. Polyethylene vial dispensers containing 20-200 mg of a 1:1 mixture caught high numbers of beetles. Captures did not decrease even after 73 days of field exposure of dispensers. At sites where both Agriotes sputator L. and A. brevis were present, the above baits were selectively catching only A. brevis, despite the fact that GB is also the main pheromone component of A. sputator, suggesting that FB has a role in reproductive isolation. In the early part of the season, traps into which the insects could both crawl and fly captured more A. brevis than designs where the insects could only fly in. Trap design was not important later in the season. This indicates the need for future development of a trap suitable for use throughout the whole season.