Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice

Abstract

Analogues of 4-phosphoryloxy-N,N-dimethyl­tryptamine (psilocybin) are being sold on recreational drug markets and developed as potential medications for psychedelic-assisted therapies. Many of these tryptamine-based psilocybin analogues produce psychedelic-like effects in rodents and humans primarily by agonist activity at serotonin 2A receptors (5-HT2A). However, the comprehensive pharmacological target profiles for these compounds compared to psilocybin and its active metabolite 4-hydroxy-N,N-dimethyl­tryptamine (psilocin) are unknown. The present study determined the receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin across a broad range of potential targets. Specifically, we examined tryptamine psychedelics with different 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl (dimethyl, methyl-ethyl, diethyl, methyl-propyl, ethyl-propyl, diisopropyl, methyl-allyl, diallyl) substitutions. Further, the psilocybin analogue 4-propionoxy-N,N-dimethyl­tryptamine (4-PrO-DMT) was administered to mice in experiments measuring head twitch response (HTR), locomotor activity, and body temperature. Overall, the present pharmacological profile screening data show that the tryptamine psychedelics target multiple serotonin receptors, including serotonin 1A receptors (5-HT1A). 4-Acetoxy and 4-propionoxy analogues of 4-hydroxy compounds displayed somewhat weaker binding affinities but similar target profiles across 5-HT receptors and other identified targets. Additionally, differential binding screen profiles were observed with N,N-dialkyl position variations across several non-5-HT receptor targets (i.e., alpha receptors, dopamine receptors, histamine receptors, and serotonin transporters), which could impact in vivo pharmacological effects of the compounds. In mouse experiments, 4-PrO-DMT displayed dose-related psilocybin-like effects to produce 5-HT2A-mediated HTR (0.3–3 mg/kg s.c.) as well as 5-HT1A-mediated hypothermia and hypolocomotion (3–30 mg/kg s.c.). Lastly, our data support a growing body of evidence that the 5-HT2A-mediated HTR induced by tryptamine psychedelics is attenuated by 5-HT1A receptor agonist activity at high doses in mice.

Psychedelic-like Activity of Norpsilocin Analogues

“…Aside from the bulky N-butyl and Ncyclohexyl substitutions, all compounds produced dose-related increases in HTRs vs vehicle controls (Figure 3, Figure S1, Table S1), with dose−response curves exhibiting the typical inverted U shape, characteristic of other psychedelic tryptamines. 5,26,27 4-HO-NALT, 4-HO-NBnT, and 4-HO-NET displayed similar potencies, producing half maximal responses (ED 50 ) at doses ranging from 1.1 to 1.4 mg/kg, while 4-HO-NPT and 4-HO-NiPT were less potent (ED 50 = 2.9−3.3 mg/ kg, Figure 3A, Table 1). Interestingly, the maximum effect (E max ) varied among the compounds (Table 1).…”

Bis(4-acetoxy-N-ethyl-N-n-propyltryptammonium) fumarate–fumaric acid (1/1)

“…4-Acetoxy-N-ethyl-N-npropyltryptamine (4-AcO-EPT) is a putative prodrug of the synthetic psychedelic, and psilocin analogue, 4-hydroxy-Nethyl-N-n-propyltryptamine (4-HO-EPT). When competitive binding assays are compared, binding is observed for 4-HO-EPT across many more receptors than 4-AcO-EPT, and significantly stronger binding is observed at most receptors where 4-AcO-EPT is also competitive (Glatfelter et al, 2023). 4-HO-EPT showed a substantial increase in in vitro functional assays for 5-HT 2A agonism over 4-AcO-EPT, with an observed EC 50 of 4.24 nM, compared to an EC 50 of 24.0 nM for the ester.…”

“…There are four trialkyltryptamine structures reported, 4-acetoxy-N,N,N-trimethyltryptamine (Chadeayne et al, 2020), 4-acetoxy-N,N-dimethyl-N-n-propyltryptamine, 4-acetoxy-N,N-dimethyl-N-isopropyltryptamine, 4-acetoxy-N,N-dimethyl-N-ethyltryptamine all as their iodide salts (Glatfelter et al, 2022a). There are also three other 4-carboxylic ester prodrug structure reported, which are 4-propionoxy-N,N-dimethyltryptamine as its hydrofumarate salt (Glatfelter et al, 2023) and two structures of the zwitterionic 4-glutarato-N,N-diisopropyltryptamine (Naeem et al, 2022).…”

The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors

“…6,10,15, and 20 mg/kg DPT on locomotor activity in WT mice; FigureS4, latency to and duration of seizures induced by 50 mg/kg NE-100 in juvenile WT and Fmr1 KO mice (PDF)Gammaitoni, A. R.; Davis, R.; Gil-Nagel, A. Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial. JAMA Neurol.…”

“…Indications under the study include but are not limited to major depressive disorder (MDD) and substance-use disorders, whereas other indications under consideration include autism spectrum disorder (ASD) and fragile X syndrome (FXS). − Despite the proliferation of clinical studies, the specific pharmacodynamic properties that contribute to the therapeutic efficacies of psychedelics are not well understood. Psychedelic tryptamines are serotonin (5-HT) 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor (5-HT 2 R) agonists, but they bind various other targets. − For example, they are 5-HT 1A and 5-HT 1B R agonists, and some, including N,N -dimethyltryptamine have direct modulatory effects in vivo on non-serotonergic receptors, including sigma1Rs. ,− This poses the question of whether targets in addition to 5-HT 2 Rs contribute to the pharmacotherapeutic effects of psychedelics. , …”