Report on a New Opioid NPS: Chemical and In Vitro Functional Characterization of a Structural Isomer of the MT-45 Derivative Diphenpipenol

Abstract

In this paper, the identification and full characterization of a novel non-fentanyl opioid sourced online, which is a member of the 1-substituted-4-(1,2-diphenylethyl)piperazine derivatives related to MT-45, is reported. The sample was sold under the name ‘diphenpipenol’, (3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylethyl]phenol), although extensive NMR analysis showed that the product obtained was actually a diphenpipenol structural isomer, (2-[4-(2-methoxyphenyl)piperazin-1-yl]-1,2-diphenylethanol). Liquid chromatography time-of-flight mass spectrometry (QTOF-MS) identified an exact mass for the protonated molecule of m/z 389.2264, with 2 prominent fragment ions (m/z 91.0567 and 150.0937), which were not reported in earlier literature describing MT-45 derivatives. The chemical characterization was finalized by gas chromatography mass-spectrometry (GC-MS), high-performance liquid chromatography diode array detector (HPLC-DAD) and Fourier-transform infrared spectroscopy (FT-IR) analyses. This product is a clear example of the trend that new non-fentanyl opioids are re-appearing on the recreational drug market to escape the recent changes in (inter)national legislation concerning fentanyl analogues. Although in this particular case the product’s potency and efficacy were relatively low, other new non-fentanyl opioids might possess stronger potencies and therefore pose greater health risks for ignorant users. The fact that the product was sold under the wrong name further demonstrates the well-known problematic issue of a mismatch between the adverted and true identity, confirming the irregularities of the online NPS market.

In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances

“…The biological activity of 11 non-fentanyl opioid NPS was evaluated using two distinct, previously reported, cell-based receptor activation assays Vasudevan et al 2020). The sensitivity and specificity of these systems was previously evaluated using a wide range of opioids Vasudevan et al 2020) and the system has since been successfully applied in different studies (Blanckaert & Cannaert et al 2020;Cannaert & Ambach et al 2018;Cannaert et al 2020;Gampfer et al 2020). The assays are based on the functional complementation of a split nanoluciferase (NanoLuc Binary Technology®, Promega).…”

“…Amongst the first to appear for online sale in this new wave were AH-7921 in 2012 and MT-45 in 2013. As from 2014, several compounds of the 'U series' (originally developed in the '70s by the Upjohn Company) became increasingly detected, with U-47700 being one of the most prevalent non-fentanyl NSOs (Blanckaert & Cannaert et al 2020;Sharma et al 2019). Between 2012 and 2018, however, the majority of NSOs hitting the drug market remained fentanyl analogues (Cannaert & Ambach et al 2018;Evans-Brown, Gallegos, and Christie 2018;Jannetto et al 2019).…”

“…Being increasingly confronted with the severe risk of fatal poisoning following the use of these substances, important efforts were made to counter this trend (Bao et al 2019;DEA 2018). The introduction of a new legislation in China in 2018 was probably the most impactful measure, as the number of new fentanyl analogues started to decrease drastically from 2018 onwards (Bao et al 2019;Blanckaert & Cannaert et al 2020). However, as exemplified by the recent emergence of brorphine, which could be considered a fentanyl analogue, drug designers still manage to find loopholes in existing legislations, even when these are 'generic' and thus aiming at covering a very wide range of analogues (Verougstraete & Vandeputte et al, under review) (Belgisch Staatsblad 2017;DEA 2018).…”

“…As a response to the recent changes in (inter)national control measures targeting fentanyl analogues, there has been a trend of non-fentanyl opioids (re)appearing on the recreational drug market (e.g. 2-Me-AP-237, isotonitazene) (Blanckaert & Cannaert et al 2020;Sharma et al 2019). While extensive literature has been published on the pharmacology and toxicology of fentanyl, fentanyl derivatives and some of the early non-fentanyl opioids (Jannetto et al 2019;Prekupec, Mansky, and Baumann 2017;Sharma et al 2019;Vasudevan et al 2020), many of these somewhat obscure, newly emerging opioids have received considerably less attention.…”

“…As a better insight into the pharmacology of NSOs may allow to prioritize international and legislative efforts towards controlling (variants of) these emerging drugs, we investigated the pharmacological profile of 11 non-fentanyl opioid NPS (Figure 1). The compounds in this panel were chosen based on their structural diversity as non-fentanyl µ-opioid receptor (MOR) agonists and their recent and/or emerging appearance on the recreational drug market (Arillotta & Schifano et al 2020;Blanckaert & Cannaert et al 2020;Sharma et al 2019;Ventura, Carvalho, and Dinis-Oliveira 2018). Although brorphine could, in essence, be considered a structural analogue of fentanyl (Verougstraete & Vandeputte et al, under review), it currently falls outside the scope of generic legislations aiming at covering fentanyl derivatives (Belgisch Staatsblad 2017;DEA 2018) and was therefore included in this study as well.…”