Search Results (6)

Background/Objectives: High-performance affinity chromatography (HPAC) was used to investigate the binding affinity of a series of synthetic cannabinoids, a widely abused class of new psychoactive substances, to human serum albumin (HSA) and obtain insights into the binding sites. To better understand the recognition mechanisms, molecular docking studies were conducted. Methods: Binding affinity was assessed through zonal elution approach Additionally, displacement chromatography with site-specific probes provided insights into the HSA binding sites of five synthetic cannabinoids. Results: That these drugs exhibit extensive binding to HSA, with values ranging from 98.7% to 99.9%. Competition for site I was observed between warfarin and four synthetic cannabinoids (5F-AMB, AB-PINACA, AMB-FUBINACA, and AB-CHMINACA). Furthermore, AB-CHMINACA also competed with L-tryptophan for site II. The binding affinity of all synthetic cannabinoids increased in the presence of (S)-ibuprofen. Molecular docking studies supported the experimental findings, reinforcing the insights gained. Conclusions: The key novelty of this study lies in analyzing, for the first time, the binding affinity of synthetic cannabinoids to HSA through HPAC and molecular docking. These results may improve our understanding of their toxicokinetic behavior and help in predicting possible competitive interactions that could influence HSA binding and, consequently, their activity and toxicity. This study is the first to describe the binding affinity of synthetic cannabinoids to HSA, elucidate their recognition mechanisms, identify binding sites, and characterize their interactions with the protein. Full article

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as ‘K2’, ‘K9’ or ‘Spice’. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings. Full article

The COVID-19 pandemic has consistently raised the number of drug seizures, in United States as in Europe. The COVID-19 pandemic has also changed the typology of seizures from “more traditional” drugs to New Psychoactive Substances (NPSs), depending on geographical area. In Europe, the most frequent NPSs are synthetic cannabinoids (SCs) and cathinones, nonetheless synthetic opioids and phenethylamines are widely used. The aim of the study is the detection of NPS and other substances of abuse available in the black market, by quali/quantitative methods in LC-MS/MS and GC-MS. From 2018 to 2021, 268 seizures occurred in total and were analyzed by the Forensic Toxicology Laboratory (FTL) of Naples (Italy). The distribution of analyzed seizures over the years is the following: 53 in 2018, 61 in 2019, 89 in 2020 and 65 during the first semester of 2021. Cannabis was the most detected drug both in hashish and marijuana seizures, followed by cocaine > heroine > prescribed drugs > ketamine–amphetamine MDMA. No NPSs were seized until June 2021, when NPSs were found in two different seizures: Case #1 showed a bar of Cannabis resin containing a low level of Δ⁹THC = 0.57% associated to SC AB-FUBINACA in 4.5%; Case #2 showed a vegetal resinous substance (Δ⁹THC = 0.27%) with SC 5F-APINACA (4.1%) associated with methadone (1.0%). The detection of NPSs is alarming evidence that can lead to an increase in the risk of overdose or other negative and unpredictable consequences, such as violent or self-harming behavior in unaware users of cannabis derivatives considered of “natural” origin. Full article

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D_7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CL_int) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min⁻¹ kg⁻¹ ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min⁻¹ kg⁻¹ ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CL_H) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min⁻¹ kg⁻¹ ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min⁻¹ kg⁻¹ ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CL_H is much slower than CL_int. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism. Full article

AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with K_i value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with K_i values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP⁺ uptake via mixed inhibition (K_i, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (K_i, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities. Full article

The endocannabinoid system represents an integrated neuronal network involved in the control of several organisms’ functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-1H-indazole-3-carboxamide (LONI11), and an antagonist, (S)-2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoic acid (LONI4), were tested in vivo in mic, to evaluate their ability to stimulate or suppress feeding behavior after intraperitoneal (i.p.) administration. For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.) and intracerebroventricular (i.c.v.) routes, respectively, were also carried out in vivo in mice to investigate the antinociceptive property at the central and peripheral levesl. We observed a significant orexant effect for LONI11 and an intense anorexant effect for (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (LONI2) and LONI4. In zymosan-induced edema and hyperalgesia, LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity. Full article