Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA

Abstract

Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB) receptor and produce effects similar to those of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for the potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects that include cardiotoxicity, seizure activity, and kidney damage, and they can cause death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI, and MN-18 were assessed for: 1) receptor binding affinity at the human CB and human CB receptors, 2) function in [S]GTPS and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for human cannabinoid receptors type-1 and type-2 and produced greater maximal effects than THC in [S]GTPS and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they probably possess subjective effects similar to those of cannabis. Notably, MDMB-FUBINACA, a methylated analog of MMB-FUBINACA, had higher affinity for CB than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB receptor, exhibiting greater efficacy than THC, and producing THC-like effects in models relevant to subjective effects in humans.

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA, and their analogs

“…The pharmacological effects of numerous SCRAs have been described in mice and rats, and include robust hypothermia, bradycardia, and hypolocomotion mediated by central CB 1 agonist activity . As anticipated from the in vitro pharmacological data, neither 5F‐PY‐PICA nor 5F‐PY‐PINACA produced physiological effects consistent with central CB 1 activity, and hypothermic effects were not observed in mice at doses up to 10 mg/kg (Figure ).…”

Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L‐valine or L‐tert‐leucine

“…Also in this study, both compounds 20 and 21 show extremely high potency as CB 1 agonists, with EC 50 values of 0.82 nM and 0.36 nM, respectively (Figure ; Table ). Whereas the estimated EC 50 value of compound 20 is in agreement with the low EC 50 value of 1.2 nM determined by Banister et al using a FLIPR ® membrane potential assay, the EC 50 value of compound 21 estimated here (0.36 nM) deviates to a larger extent from the result obtained by Banister et al (3.9 nM) but is in good agreement with the EC 50 value of 0.26 nM, as determined by [ 35 S]GTPγS assay by Gamage et al As mentioned earlier, different EC 50 value outcomes can be explained by the implementation of different functional signaling assays, different cell lines (CHO vs HEK293T cells) or even biased signaling. Hydrolysis of the terminal moieties (primary amide and methylester for ADB‐FUBINACA ( 20 ) and MDMB‐FUBINACA ( 21 ), respectively) was found to be a common major metabolic pathway for both parent compounds .…”

“…Further adding to the complexity of the SCRA problem is that, in addition to the rapid and constant emergence of new SCRAs, relatively little is known about the pharmacology of these SCRAs and their metabolites. More particularly, few studies have focused on the pharmacological characteristics of hydrolysis metabolites . Recently, there has been an increased interest, since knowledge about SCRA metabolite activity data might empower forensic laboratories to elaborate on the possible contributory role of these metabolites in human intoxications and in side‐effects related to SCRAs.…”

New psychoactive substances: Pharmacology influencing UK practice, policy and the law

“…This game of cat‐and‐mouse continued: the chemists went back to the drawing board—in this case molecular modelling—and made a further set of compounds many of which had never been made before so there were no safety data even in animals . Not surprisingly, these compounds turned out to be even worse than the previous ones often causing severe psychotic reactions, seizures and heart attacks from Q/T prolongation .…”