Current Pharmaceutical Design - Volume 28, Issue 32, 2022

Background: Over the past few years, an emerging number of new psychoactive substances (NPSs) entered the illicit market. NPSs are designed to resemble the effects of classical drugs of abuse, reinforcing their effects and duration. Among the most abused NPS, synthetic cannabinoids are cannabinoid receptor agonists (SCRAs) that mimic the effect of the main psychotropic phytocannabinoid Δ9-tetrahydrocannabinol (THC). Methods: We herein reviewed the international literature to provide available information on the newest SCRAs generation. Results: Compared to the previous SCRAs generations, the structures of the last generation result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be mainly responsible for the psychoactive effects of THC and its analogues. Accordingly, these more potent cannabimimetic effects may increase the number of adverse reactions such as neurological disorders (e.g., psychosis, agitation, irritability, paranoia, confusion, and anxiety), psychiatric episodes (e.g., hallucinations, delusions, self-harm), other physical conditions (e.g., tachycardia, hypertension, arrhythmia, chest pain, nausea, vomiting, and fever) and deaths. In the last decade, more than a hundred SCRAs from different chemical classes emerged on the illicit web market. SCRAs have been thoroughly studied: they were physico-chemically characterized, and pharmaco-toxicological characteristics were investigated. The last SCRAs generations include increasingly potent and toxic compounds, posing a potential health threat to consumers. Conclusion: From November 2017 to February 2021, at least 20 new “fourth-generation” SCRAs were formally reported to international drug agencies. Our understanding of the neurotoxicity of these compounds is still limited due to the lack of global data, but their potency and their toxicity are likely higher than those of the previous generations.

Background: The presence of the synthetic cannabinoid receptor agonist MDMB-4en-PINACA in adulterated low-THC cannabis products was recently highlighted in several reports. Moreover, numerous intoxication cases involving MDMB-4en-PINACA have been described. Objective: In order to monitor the diffusion of cannabis products containing MDMB-4en-PINACA in our territory, a total of 358 cannabis-derived samples (213 vegetal material and 145 resins) seized in the period November 2020 - February 2021 in the western Piedmont Area (Italy) was analyzed. Methods: General screening analyses for traditional and synthetic cannabinoids were performed by a GC-MS device operating in full scan mode (40-600 amu). The MDMB-4en-PINACA was quantified by means of a specific GC-SIM-MS protocol purposely developed and validated, while the quantification of THC, CBD, and CBN was carried out by a GC-SIM-MS method routinely employed in our laboratory. Results: MDMB-4en-PINACA was detected in 12 out of 358 samples (3.4% of the total). Among these, the molecule was found in 11 vegetal materials and in one resin sample. Considering solely the analysis of the 213 herb products, a positive rate of 5.2% was found for the presence of MDMB-4en-PINACA in these samples. MDMB-4en-PINACA was found in the seized materials at concentration levels ranging from 0.4 up to 6.3 mg/g (mean 2.5 mg/g; median 1.7 mg/g). Concerning the traditional cannabinoids, the THC concentration was in the interval 3-43 mg/g (mean 12 mg/g; median 7 mg/g), while CBD was found at higher concentrations in all specimens, specifically in the range 47-140 mg/g (mean 87 mg/g; median 80 mg/g). Conclusion: The adulteration of low-THC cannabis products with synthetic cannabinoid receptor agonists is widespread today. Since these substances are potentially more toxic than THC, their consumption poses a high risk of overdose for unaware users and a health-threatening situation. This study confirmed the sporadic presence on the market of CBD-prevalent cannabis products adulterated with MDMB-4en-PINACA.

Background: The detection of new designer benzodiazepines in biological fluids and tissues, together with the traditional ones, could represent an important analytical update for laboratories performing clinical and forensic toxicological analysis. Objective: A liquid chromatography tandem mass spectrometry method (LC-MS/MS) has been developed, fully validated, and applied to a cohort of real urine samples collected from patients under withdrawal treatment and from intoxication cases. Methods: 100 μL urines were added to a buffer solution containing deuterated internal standards; the samples were then extracted through a liquid/liquid procedure, dried under a nitrogen stream, and reconstituted in mobile phase. The chromatographic separation was performed in reverse phase through a C18 column with gradient elution. Mass spectrometry operated in positive polarization and multiple reaction monitoring mode. Results: 25 molecules were optimized for instrumental analysis: 9 designer benzodiazepines and 16 traditional compounds (parent drugs and main metabolites). Sensitivity, specificity, linearity, accuracy, imprecision, recovery, matrix effects, and carry-over have been evaluated for all molecules. Only cinazepam did not satisfy all acceptance criteria for validation. 10 among the 50 analyzed samples tested positive for at least one of the monitored molecules. In particular, two different samples collected from the same case provided positive results for flubromazepam, a designer benzodiazepine. Conclusion: The method was proven to be useful in detecting not only traditional benzodiazepines but also new designer ones. The identification of a New Psychoactive Substance in real samples confirmed that analytical procedures should be updated to include as many substances as possible.

Background: Previous studies have reported that benzodiazepines (BZDs) seem to enhance euphoric and reinforcing properties of opioids in opioid users so that a direct effect on opioid receptors has been postulated, together with a possible synergistic induction of severe side effects due to co use of BDZs and opioids. This is particularly worrisome given the appearance on the market of designer benzodiazepines (DBZDs), whose activity/toxicity profiles are scarcely known. Objectives: This study aimed to evaluate, through computational studies, the binding affinity (or lack thereof) of 101 DBZDs identified online on the kappa, mu, and delta opioid receptors (K, M, DOR); and to assess whether their mechanism of action could include activation of the latter. Methods: MOE® was used for the computational studies. Pharmacophore mapping based on strong opioids agonist binders’ 3D chemical features was used to filter the DBZDs. Resultant DBZDs were docked into the crystallised 3D active conformation of KOR (PDB6B73), DOR (PDB6PT3) and MOR (PDB5C1M). Co-crystallised ligands and four strong agonists were used as reference compounds. A score (S, Kcal/mol) representative of the predicted binding affinity, and a description of ligand interactions were obtained from MOE®. Results: The docking results, filtered for S < -8.0 and the interaction with the Asp residue, identified five DBZDs as putative binders of the three ORs : ciclotizolam, fluloprazolam, JQ1, Ro 48-6791, and Ro 48-8684. Conclusion: It may be inferred that at least some DBZDs may have the potential to activate opioid receptors. This could mediate/increase their anxiolytic, analgesic, and addiction potentials, as well as worsen the side effects associated with opioid co-use.

Background: MDPV (3,4-methylenedioxypyrovalerone) is a synthetic stimulant that blocks transmitter uptake at transporters for dopamine and norepinephrine. Less is known about MDPV pharmacokinetics, especially with respect to brain concentrations of the drug and its metabolites. Objectives: The goal of the present study was: 1) to determine brain concentrations of MDPV and its metabolites, 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxy-pyrovalerone (4-OH-3-MeOPV), after administration of MDPV, and 2) to relate brain pharmacokinetic measures to pharmacodynamic endpoints in the same subjects. Methods: Male Sprague-Dawley rats (300-400 g) received s.c. MDPV injection (1, 2, or 4 mg/kg) or its saline vehicle. Groups of rats were decapitated at 40 min and 240 min postinjection. Locomotor behavior was rated before decapitation, and the core temperature was obtained. Plasma and frontal cortex were analyzed to quantitate MDPV and its metabolites. Striatal samples were analyzed to measure dopamine, serotonin (5-HT), and their metabolites. Results: MDPV displayed brain-to-plasma ratios greater than 1 (range 8.8-12.1), whereas 3,4-catechol-PV and 4-OH-3-MeO-PV showed ratios less than 1 (range 0-0.3). MDPV increased behavioural scores reflective of locomotor stimulation at 40 and 240 min and produced slight hyperthermia at 240 min. MDPV had no effect on striatal dopamine but produced an increase in the metabolite homovanillic acid (HVA). Brain MDPV concentrations were positively correlated with behavioural scores and striatal HVA but not with other endpoints. Conclusion: The behavioural effects of MDPV are related to brain concentrations of the parent drug and not its metabolites. The modest effects of MDPV on monoamine systems suggest that other non-monoamine mechanisms may contribute to the effects of the drug in vivo.

Heat shock protein 90 (Hsp90) is a chaperone protein that prevents many other proteins from aggregating by folding them in a certain way. Hsp90 consists of three structural domains: N-terminal, middle and C-terminal domains. Hsp90 has many activities in numerous proteins and signaling pathways like chimeric fusion proteins, steroid hormone receptors, tumor suppressor genes, and cell cycle regulatory proteins. The role of Hsp90 is not only in cancer but also in other diseases like COVID-19, leishmaniasis, diabetes, flavi virus, systemic sclerosis, grass carp reovirus, psoriasis, malaria, cardiac fibrosis, and alcohol-related liver diseases. This review is a compilation of the pharmacological profile of Hsp90 inhibitors, problems associated with them, and suggested remedies for the same.

The incidence of colorectal cancer (CRC) has significantly increased in recent decades, which has made this disease an important global health issue. Despite many efforts, there is no useful prognostic or diagnostic biomarker for CRC. Heat shock protein 27 (Hsp27) is one of the most studied members of the Hsp family. It has attracted particular attention in CRC pathogenesis since it is involved in fundamental cell functions for cell survival. Evidence shows that Hsp27 plays important role in CRC progression and metastasis. Hsp27 overexpression has been observed in CRC and is suggested to be associated with CRC's poor prognosis. In the present review, we focus on the current knowledge of the role of Hsp27 in CRC carcinogenesis and the underlying mechanisms. In addition, we discuss the value of targeting Hsp27 in CRC treatment.