Receptor binding profiles and behavioral pharmacology of ring-substituted N,N-diallyltryptamine analogs

Abstract

Substantial effort has been devoted toward understanding the psychopharmacological effects of tryptamine hallucinogens, which are thought to be mediated by activation of 5-HT and 5-HT receptors. Recently, several psychoactive tryptamines based on the N,N-diallyltryptamine (DALT) scaffold have been encountered as recreational drugs. Despite the apparent widespread use of DALT derivatives in humans, little is known about their pharmacological properties. We compared the binding affinities of DALT and its 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 5-methoxy-, 5-methoxy-2-methyl-, 5-fluoro-, 5-fluoro-2-methyl-, 5-bromo-, and 7-ethyl-derivatives at 45 receptor and transporter binding sites. Additionally, studies in C57BL/6 J mice examined whether these substances induce the head twitch response (HTR), a 5-HT receptor-mediated response that is widely used as a behavioral proxy for hallucinogen effects in humans. Most of the test drugs bound to serotonin receptors, σ sites, α-adrenoceptors, dopaminergic D receptors, histaminergic H receptors, and the serotonin transporter. DALT and several of the ring-substituted derivatives were active in the HTR assay with the following rank order of potency: 4-acetoxy-DALT > 5-fluoro-DALT > 5-methoxy-DALT > 4-hydroxy-DALT > DALT > 5-bromo-DALT. 2-Phenyl-DALT, 5-methoxy-2-methyl-DALT, 5-fluoro-2-methyl-DALT, and 7-ethyl-DALT did not induce the HTR. HTR potency was not correlated with either 5-HT or 5-HT receptor binding affinity, but a multiple regression analysis indicated that 5-HT and 5-HT receptors make positive and negative contributions, respectively, to HTR potency (R = 0.8729). In addition to supporting the established role of 5-HT receptors in the HTR, these findings are consistent with evidence that 5-HT activation by tryptamine hallucinogens buffers their effects on HTR. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Designer drugs: mechanism of action and adverse effects

“…Tryptamine designer drugs have been shown to bind to 5-HT 2C receptors but with slightly lower affinity compared with 5-HT 2A receptors (Rickli et al 2016). In addition to their primary effects at serotonergic receptors, tryptamines have been shown to bind to various targets in vitro, including adrenergic, dopaminergic, and histaminergic receptors (Klein et al 2018;Rickli et al 2016). Furthermore, unlike phenethylamine or lysergamide psychedelics, many tryptamine psychedelics interact with monoamine transporters at pharmacologically relevant concentrations.…”

Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice

“…Mescaline induced the HTR with an ED 50 of 6.51 mg/kg, which is equivalent to a molar potency of 26.3 µmol/kg. Similar to other hallucinogens (Fantegrossi et al, 2010;Fantegrossi et al, 2005;Fantegrossi et al, 2006;Klein et al, 2018;Halberstadt et al, 2018a), the response to mescaline and most of the other compounds followed an inverted-U-shaped dose-response function. Escaline (the 4-ethoxy homologue of mescaline) and proscaline (the 4-propoxy homologue) also induced the HTR.…”

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

“…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 …”