Novel Psychoactive Substances: : the pharmacology of stimulants and hallucinogens

This is an Accepted Manuscript of an article published by Taylor & Francis in Expert Review of Clinical Pharmacology, on March 2016, available online at doi: : http://www.tandfonline.com/doi/full/10.1586/17512433.2016.1167597.There are increasing levels of concern relating to the rapidly evolving novel psychoactive substances/NPS and web markets’ scenarios. The paper aims at providing an overview of the clinical pharmacological issues related to some of the most popular NPS categories, e.g. stimulants and hallucinogens. NPS intake is typically associated with the imbalance of a complex range of neurotransmitter pathways/receptors, namely: dopamine; cannabinoid/CB1; and 5-HT2A. The intake is almost invariably undetectable with standard screening tests. Hence, it may frequently occur that the acute management of NPS misusers will need to focus on decreasing levels of both self/outward-directed aggression and agitation. Benzodiazepines may be considered as first line treatment. Alternatively, propofol and/or antipsychotics can be administered. Focus will be as well on treatment of possible rhabdomyolysis and hyperthermia. Indeed, future studies should inform better tailored management/treatment strategies.Peer reviewedFinal Accepted Versio

Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

Differences in host-plant related chemical communication of the flea beetles Phyllotreta cruciferae Goeze and Ph. vittula Redtenbacher (Coleoptera, Chrysomelidae)

Remarkable differences have been found in host-plant related chemical communication between Phyllotreta cruciferae Goeze and Ph. vittula Redtenbacher (Coleoptera, Chrysomelidae). In preliminary screenings sizeable catches of Ph. vittula were recorded in traps baited with either 3-butenyl isothiocyanate, or a quternary mixture of 2-butenyl-, phenethyl-, 3-butenyl-and butyl isothiocyanates. Later studies revealed that Ph. vittula responded better to the above isothiocyanate mixture, than to allyl isothiocyanate, while Ph. cruciferae catches were always greater in allyl isothiocyanate baited traps. Of the four isothiocyanates in the mixture, 3-butenyl isothiocyanate may predominantly be responsible for attractivity of the mixture towards Ph. vittula .As such differences in isothiocyanate preference may occur also in other flea beetle species, for practical applications more efficient, selective and sensitive baits and traps may be developed in the future based on improved knowledge of the chemical communication of flea beetles and through optimal combination of effective isothiocyanate compounds. Both Ph. cruciferae and Ph. vittula rank among the most important pest flea beetles in Europe

Development of Trapping Tools for Detection and Monitoring of Diabrotica v. virgifera in Europe

Trap designs baited with the synthetic sex pheromone have been optimized for trapping of the western corn rootworm Diabrotica v. virgifera LeConte (Coleoptera: Chrysomelidae) (WCR), which has recently been introduced into Europe. The best trap design proved to be the sticky “cloak” trap (code name “PAL”), which catches only males, and is being used in many countries of Europe for detection and monitoring the spread of the new pest. Preliminarily the range of attraction (as defined by Wall and Perry, 1987) of the pheromone traps was estimated to be <10 m. The performance of yellow sticky plates (used by others for monitoring of the pest) was insignificant as compared to the activity of the pheromone baited traps, and yellow colour had no discernible effect on catches in pheromone traps. The known floral lure of WCR containing 4-methoxy-cinnamaldehyde and indole proved to be active also towards the population in Europe, attracting both females and males. Yellow colour slightly increased catches by the floral lure, hence a yellow sticky “cloak” trap has been developed (code name PALs). Pheromone baited PAL traps caught a total of about 4 times more beetles than the floral baited PALs, which latter however appeared to be preferentially active for females. When placed into the same trap, the pheromonal and floral lures did not interfere with each other's activity

Synthesis and in vitro evaluation of BBB permeability, tumor cell uptake, and cytotoxicity of a series of carboranylporphyrin conjugates.

A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr-D-Arg-Phe-β-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50>400 μM) and low phototoxicity (IC50>100 μM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient

Use of reduced graphs to encode bioisosterism for similarity-based virtual screening

This paper describes a project to include explicit information about bioisosteric equivalences between pairs of fragment substructures in a system for similarity-based virtual screening. Data from the BIOSTER database show that reduced graphs provide a simple way of encoding known bioisosteric equivalences in a manner that can be used during similarity searching. Scaffold-hopping experiments with the WOMBAT database show that including such information enables similarities to be identified between the reference structures and active structures from the database that contain different, but equivalent, fragment substructures. However, such equivalences also contribute to the similarities between the reference structures and inactives, and the latter equivalences can swamp those involving the actives. This presents serious problems for the routine use of information about bioisosteric fragments in similarity-based virtual screening