Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran (“FLY”) and benzodifuran (“DragonFLY”) analogs

Abstract

In recent years, rigid analogues of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b ’]difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 μmol/kg) and 2C-B (ED50 = 2.43 μmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 μmol/kg) and 2C-B-DFLY (ED50 = 1.07 μmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 μmol/kg) and 2C-B-FLY (ED50 = 1.79 μmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.

Return of the lysergamides. Part V: Analytical and behavioural characterization of 1‐butanoyl‐d‐lysergic acid diethylamide (1B‐LSD)

“…1P‐LSD also showed reduced potency compared to LSD when evaluated in HTR experiments . Generally, the potency relationships for hallucinogens in the mouse HTR paradigm closely parallel the human hallucinogenic data . Interpretation of the HTR potency data, however, is complicated by the possibility that 1B‐LSD serves as a pro‐drug for LSD, as indicated by in vitro assays .…”

“…If 1B‐LSD is not the active species and must be hydrolyzed to LSD then extrapolation of mouse potency data to humans is complicated by the possibility of species differences in metabolic enzymes. Nevertheless, although 1B‐LSD is not as potent as LSD in mice, it still has relatively high potency compared to many other hallucinogens …”

“…15 Generally, the potency relationships for hallucinogens in the mouse HTR paradigm closely parallel the human hallucinogenic data. 27,30,31 Interpretation of the HTR potency data, however, is complicated by the possibility that 1B-LSD serves as a pro-drug for LSD, as indicated by in vitro assays. 12 If 1B-LSD is not the active species and must be hydrolyzed to LSD then extrapolation of mouse potency data to humans is complicated by the possibility of species differences in metabolic enzymes.…”

“…Nevertheless, although 1B-LSD is not as potent as LSD in mice, it still has relatively high potency compared to many other hallucinogens. 30 Clinical studies are warranted to evaluate the potency of 1B-LSD in humans and to define its abuse potential as well as the qualitative nature of its effects.…”

Phenethylamine‐derived new psychoactive substances 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings

“…A series of FLY compounds were originally synthesized to study 5‐HT 2A receptor function and 2‐(4‐bromo‐2,3,6,7‐tetrahydrofuro[2,3‐f][1]benzofuran‐8‐yl)ethanamine (2C‐B‐FLY) was shown to potently bind to the human 5‐HT 2A receptor . 2C‐B‐FLY was first reported to the early warning system on NPS implemented by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2007 and several times afterwards .…”