Gavin McLaughlin

Benzodiazepines are a class of compounds used clinically to treat a variety of conditions including anxiety and insomnia. Their potential for abuse has led to a surge in their availability on the illegal drugs market. End users often rely on markings on illicit tablets to identify their contents. However, falsified tablets mimicking genuine pharmaceutical preparations often contain ingredients that differ from what people believe they are taking. The absence of any quality control of the content, purity, or strength of fake tablets can result in adverse effects or even fatal outcomes. In recent years, drug seizures involving illicit round yellow tablets marked “5” on one side and “5617” below a scoreline on the reverse have been submitted to Forensic Science Ireland (FSI) by An Garda Síochána (Irish Police) from throughout the Republic of Ireland. These findings relate to 26 different seizures; the cumulative tablet total seized was in excess of 20,000, and the total number of tablets of this description analyzed at FSI was 141. Irish users assume that the active ingredient present was diazepam. The qualitative analytical results for these tablets are reported. All tablets were found to contain 2‐methylamino‐5‐chlorobenzophenone. In addition, the tablets contained either 2‐amino‐3‐(2‐chlorobenzoyl)‐5‐ethylthiophene or etizolam or both. The constituents were present in varying relative amounts in visually similar tablets. Neither 2‐amino‐5‐chlorobenzophenone nor 2‐amino‐3‐(2‐chlorobenzoyl)‐5‐ethylthiophene had previously been found in tablets analyzed at FSI.

The availability of new psychoactive substances on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS drug market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM) and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic and mass spectrometric platforms. Pharmacological studies were conducted in order to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to MDMA. The combination of test purchases, analytical characterization, targeted organic synthesis and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace.

This perspective examines amphetamine importations into Ireland. Some novel by-products were detected and linked to a change in the method of production of P2P from APAAN. These by-products remained present during subsequent Leuckart reaction conditions. Novel by-products from substituted cathinone synthesis reactions were also isolated and characterized.

Misuse of (±)‐threo‐methylphenidate (methyl‐2‐phenyl‐2‐(piperidin‐2‐yl)acetate; Ritalin®; MPH) has long been acknowledged, but the appearance of MPH analogs in the form of ‘research chemicals’ has only emerged in more recent years. 4‐Fluoromethylphenidate (4F‐MPH) is one of these recent examples. This study presents the identification and analytical characterization of two powdered 4F‐MPH products that were obtained from an online vendor in 2015. Interestingly, the products appeared to have originated from two distinct batches given that one product consisted of (±)‐threo‐4F‐MPH isomers whereas the second sample consisted of a mixture of (±)‐threoand (±)‐erythro4F‐MPH. Monoamine transporter studies using rat brain synaptosomes revealed that the biological activity of the 4F‐MPH mixture resided with the (±)‐threoand not the (±)‐erythroisomers based on higher potencies determined for blockage of dopamine uptake (IC₅₀4F‐MPH_mixture = 66 nM vs. IC₅₀(±)‐threo = 61 nM vs. IC₅₀(±)‐erythro = 8,528 nM) and norepinephrine uptake (IC₅₀4F‐MPH_mixture = 45 nM vs. (±)‐threo = 31 nM vs. IC₅₀(±)‐erythro = 3,779 nM). In comparison, MPH was three times less potent than (±)‐threo‐4F‐MPH at the dopamine transporter (IC₅₀ = 131 nM) and around 2.5 times less potent at the norepinephrine transporter (IC₅₀ = 83 nM). Both substances were catecholamine selective with IC₅₀values of 8,805 nM and >10,000 nM for (±)‐threo‐4F‐MPH and MPH at the serotonin transporter. These findings suggest that the psychostimulant properties of (±)‐threo‐4F‐MPH might be more potent in humans than MPH. Copyright © 2017 John Wiley & Sons, Ltd.

2‐[(Diphenylmethyl)sulfinyl]acetamide (modafinil) is commonly prescribed for the treatment of narcolepsy. Increasing popularity and off‐label use as a cognitive enhancer has resulted in a reputation as an intelligence boosting ‘wonder drug'. Common alternatives available from online shops and other retail outlets include 2‐[(diphenylmethyl)sulfinyl]‐N‐hydroxyacetamide (adrafinil), 2‐{[bis(4‐fluorophenyl)methyl]sulfinyl}acetamide (CRL‐40,940), 2‐{[bis(4‐fluorophenyl)methyl]sulfinyl}‐N‐hydroxyacetamide (CRL‐40,941), and N‐methyl‐4,4‐difluoro‐modafinil (modafiendz), respectively. Gas chromatography‐mass spectrometry (GC‐MS) is a common tool used in forensic and clinical analysis but there is a potential for inducing analysis‐related ambiguities. This study reports on the thermal degradation of modafinil, modafinic acid, adrafinil, CRL‐40,940, and CRL‐40,941 due to exposure to the heated GC injection port dissolved in a variety of solvents. Key degradation products common to modafinil, modafinic acid, and adrafinil analysis included diphenylmethanol and 1,1,2,2‐tetraphenylethane (TPE), the latter of which was verified by its synthesis and characterization by x‐ray crystallography. The investigated compounds were also characterized by ¹H and ¹³C NMR. Diphenylmethane and thiobenzophenone were also identified in some instances. TPE formation was suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate. Correspondingly, the fluorinated TPE analogue was formed during heat‐induced degradation of modafiendz, CRL‐40,940 and CRL‐40,941, respectively. When a mixture of modafinil (non‐fluorinated) and modafiendz (fluorinated) were subjected to GC analysis, 4,4'‐(2,2‐diphenylethane‐1,1‐diyl)bis(fluorobenzene) was detected as a third cross reaction product in addition to the two expected TPE analogues. These observations served as a reminder that the seemingly straightforward implementation of GC‐MS analysis can lead to challenges during routine analysis.

3‐Methoxy‐2‐(methylamino)‐1‐(4‐methylphenyl)propan‐1‐one (mexedrone) appeared in 2015 and was advertised by UK Internet retailers as a non‐controlled mephedrone derivative (2‐(methylamino)‐1‐(4‐methylphenyl)propan‐1‐one), which was of particular interest to countries who operate generic drugs legislation. This study describes the synthesis and analytical characterization of mexedrone and the differentiation from its isomer, N‐methoxymephedrone, which was predicted to be a suitable candidate before the identity of mexedrone was revealed. A full analytical characterization is described using various chromatographic, spectroscopic and mass spectrometric platforms and X‐ray crystal structure analysis. The analytical data obtained for a vendor sample were consistent with the synthesized mexedrone reference standard and analytical differentiation between the mexedrone and N‐methoxymephedrone positional isomers was achieved. Furthermore, α‐chloromethylmephedrone was identified as a by‐product during mexedrone synthesis. All three substances were also studied for their uptake and releasing properties at dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) using in vitro monoamine transporter assays in rat brain synaptosomes and compared to mephedrone. Mexedrone was a weak non‐selective uptake blocker with IC₅₀ values in the low μM range. It was also devoid of releasing activity at DAT and NET but displayed weak releasing activity at SERT (EC₅₀ = 2.5 μM). The isomer N‐methoxymephedrone was found to be a weak uptake blocker at DAT, NET and SERT, as well as a fully efficacious substrate‐type releasing agent across all three transporters with EC₅₀ values in the low micromolar range. The synthesis by‐product α‐chloromethylmephedrone was inactive in all assays. Copyright © 2016 John Wiley & Sons, Ltd.

Recently, the pyrazole‐containing synthetic cannabinoid N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐(cyclohexylmethyl)‐3‐(4‐fluorophenyl)‐1H‐pyrazole‐5‐carboxamide (3,5‐AB‐CHMFUPPYCA) has been identified as a ‘research chemical’ both in powdered form and as an adulterant present in herbal preparations. Urine is the most common matrix used for abstinence control and the extensive metabolism of synthetic cannabinoids requires implementation of targeted analysis. The present study describes the investigation of the in vitro phase I metabolism of 3,5‐AB‐CHMFUPPYCA and its regioisomer 5,3‐AB‐CHMFUPPYCA using pooled human liver microsomes. Metabolic patterns of both AB‐CHMFUPPYCA isomers were qualitatively similar and dominated by oxidation of the cyclohexylmethyl side chain. Biotransformation to monohydroxylated metabolites of high abundance confirmed that these species might serve as suitable targets for urine analysis. Furthermore, since synthetic cannabinoids are commonly administered by smoking and because some metabolites can also be formed as thermolytic artefacts, the stability of both isomers was assessed under smoking conditions. Under these conditions, pyrolytic cleavage of the amide bond occurred that led to approximately 3 % conversion to heat‐induced degradation products that were also detected during metabolism. These artefactual ‘metabolites’ could potentially bias in vivo metabolic profiles after smoking and might have to be considered for interpretation of metabolite findings during hair analysis. This might be relevant to the analysis of hair samples where detection of metabolites is generally accepted as a strong indication of drug use rather than a potential external contamination. Copyright © 2016 John Wiley & Sons, Ltd.

The knowledge captured in patent and scientific research literature stimulates new ideas and fosters new drug development efforts. Manufacturers and entrepreneurs dedicated to the sale of ‘research chemicals’ and/or new psychoactive substances (NPS) also make use of access to information to identify, prepare, and launch a range of new substances. One of the most recent compounds to appear on the NPS market is the phenmetrazine analog 3‐fluorophenmetrazine (3‐FPM) which represents one of many phenylmorpholines designed to explore treatment options in areas such as obesity and drug dependence. The anorectic drug analogs phenmetrazine and phendimetrazine, used as prescription medicines before they were withdrawn, feature amphetamine‐like properties associated with monoamine release. Available data on 3‐FPM suggest that the effects might show mechanistic overlaps. This study describes the synthesis and extensive analytical characterization of 3‐FPM and its differentiation from synthesized ortho‐ and para‐ substituted isomers, 2‐FPM and 4‐FPM, respectively. This study was triggered by the purchase of five powdered samples advertised as 3‐FPM by five different Internet vendors based in the United Kingdom. The analytical data obtained for the vendor samples were consistent with the synthesized 3‐FPM standard and differentiation between all three isomers was possible. The presence of positional isomers and the absence of suitable reference material can cause difficulties in the day‐to‐day operation of forensic work and given the rate at which many of the newly emerging NPS appear on the market, a comprehensive approach is needed when attempting to decipher the identity of NPS arriving onto the drug market. Copyright © 2016 John Wiley & Sons, Ltd.

1‐Phenyl‐2‐propanone (P2P) is an internationally monitored precursor that has become increasingly difficult for illicit amphetamine producers to source, which means that alternative routes to its preparation have become increasingly important. One such approach includes the hydrolysis of alpha‐phenylacetoacetonitrile (APAAN) with sulfuric acid. Previously, we reported the identification of 4,6‐dimethyl‐3,5‐diphenylpryid‐2‐one following implementation of hydrolysis conditions and it was proposed that this compound might serve as one route specific by‐product in the APAAN to P2P conversion. This study continued to explore the presence of impurities formed during this conversion and expanded also into a second route of P2P synthesis starting from alpha‐methylstyrene (AMS). All P2P products underwent the Leuckart procedure to probe the presence of P2P‐related impurities that might have carried through to the final product. Two by‐products associated with the APAAN hydrolysis route to P2P were identified as 2,3‐diacetyl‐2,3‐diphenylsuccinonitrile (1) and 2‐methyl‐1‐phenyl‐1,3‐dicarbonitrile‐1H‐indene (2), respectively. Two by‐products associated with the AMS route to P2P and subsequent Leuckart reaction were 1,1,3‐trimethyl‐3‐phenyl‐2,3‐dihydro‐1H‐indene (3) and 1‐phenyl‐N‐(phenylethyl)propan‐2‐amine (4), respectively. The two indenes (2 and 3) identified in synthesized amphetamine originating from P2P suggested that it might be possible to differentiate between the two synthetic routes regarding the use of APAAN and AMS. Furthermore, the association of these compounds with amphetamine production appears to have been reported for the first time. The presence of compounds 1 – 4 in seized amphetamine samples and waste products could facilitate the suggestion whether APAAN or AMS were employed in the synthesis route to the P2P. Copyright © 2016 John Wiley & Sons, Ltd.