Bis(4-acetoxy-N-ethyl-N-n-propyl-tryptammonium) fumarate-fumaric acid (1/1).

The solid-state structure of the title salt/adduct (systemic name: bis-{[2-(4-acet-yloxy-1H-indol-3-yl)eth-yl](eth-yl)propyl-aza-nium} but-2-enedioate-(E)-butenedioic acid (1/1)), 2C17H25N2O2 +·C4H2O4 2-·C4H4O4, was determined by single-crystal X-ray diffraction. The asymmetric unit consists of a singly protonated tryptammonium cation, one half of a fumarate dianion and one half of a fumaric acid mol-ecule. In the crystal, the ions and mol-ecules are linked together in infinite chains propagating along [001] through a series of N-H⋯O and O-H⋯O hydrogen bonds.

N-Cyclo-hexyl-tryptamine: freebase, bromide and fumarate.

The solid-state structures of N-cyclo-hexyl-tryptamine (I) {systematic name: N-[2-(1H-indol-3-yl)eth-yl]cyclo-hexa-namine}, C16H22N2, and two of its salts, N-cyclo-hexyl-tryptammonium bromide (II) {systematic name: N-[2-(1H-indol-3-yl)eth-yl]cyclo-hexa-naminium bromide}, C16H23N2 +·Br-, and N-cyclo-hexyl-tryptammonium fumarate (III) (systematic name: bis-{N-[2-(1H-indol-3-yl)eth-yl]cyclo-hexa-naminium} (2E)-but-2-enedioate), 2C16H23N2 +·C4H2O4 2-, were determined by single-crystal X-ray diffraction. The freebase compound forms infinite chains along [010] through N-H⋯N hydrogen bonds. The bromide salt is held together by N-H⋯Br inter-actions in two-dimensional sheets along (001). The fumarate salt is held together in infinite three-dimensional frameworks by N-H⋯O hydrogen bonds.

A "Magic Mushroom" Multi-Product Sesquiterpene Synthase.

Psilocybe "magic mushrooms" are chemically well understood for their psychotropic tryptamines. However, the diversity of their other specialized metabolites, in particular terpenoids, has largely remained an open question. Yet, knowledge on the natural product background is critical to understand if other compounds modulate the psychotropic pharmacological effects. CubA, the single clade II sesquiterpene synthase of P. cubensis, was heterologously produced in Escherichia coli and characterized in vitro, complemented by in vivo product formation assays in Aspergillus niger as a heterologous host. Extensive GC-MS analyses proved a function as multi-product synthase and, depending on the reaction conditions, cubebol, ß-copaene, δ-cadinene, and germacrene D were detected as the major products of CubA. In addition, mature P. cubensis carpophores were analysed chromatographically which led to the detection of ß-copaene and δ-cadinene. Enzymes closely related to CubA are encoded in the genomes of various Psilocybe species. Therefore, our results provide insight into the metabolic capacity of the entire genus.

N-Methyl-serotonin hydrogen oxalate.

The solid-state structure of N-methyl-serotonin {systematic name: [2-(5-hy-droxy-1H-indol-3-yl)eth-yl](meth-yl)aza-nium hydrogen oxalate}, C11H15N2O+·C2HO4 -, is reported. The structure possesses a singly protonated N-methylserotonin cation and one hydrogen oxalate anion in the asymmetric unit. In the crystal, the mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds into a three-dimensional network.

Synthesis and structure of 4-hy-droxy-N-iso-propyl-tryptamine (4-HO-NiPT) and its precursors.

The title compound, 4-hy-droxy-N-iso-propyl-tryptamine (4) or 4-HO-NiPT (systematic name: 3-{2-[(propan-2-yl)amino]-eth-yl}-1H-indol-4-ol), C13H18N2O, was synthesized in three steps from 4-benzyl-oxyindole (1) (systematic name: 4-phen-oxy-1H-indole), C15H13NO. (1) was treated with oxalyl chloride and iso-propyl-amine to produce N-isopropyl-4-benz-yloxy-3-indole-glyoxyl-amide (2) {systematic name: 2-[4-(benz-yloxy)-1H-indol-3-yl]-2-oxo-N-(propan-2-yl)acet-amide}, C20H20N2O3. (2) was reduced to generate 4-benz-yloxy-N-iso-propyl-tryptamine (3) or 4-HO-NiPT, which was characterized as its chloride salt 4-benz-yloxy-N-iso-propyl-tryptammonium chloride (3a) (systematic name: {2-[4-(benz-yloxy)-1H-indol-3-yl]eth-yl}(propan-2-yl)aza-nium chloride), C20H25N2O·Cl. Finally the benzyl group of (3) was removed via hydrogenation to generate 4-HO-NiPT. The crystal structures of the title compound and all three synthetic precursors are presented.

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

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.

Bis(oxotremorine) fumarate bis-(fumaric acid).

The title compound, bis-(oxotremorine) fumarate bis-(fumaric acid) {systematic name: 1-[4-(2-oxopyrrolidin-1-yl)but-2-yn-yl]pyrrolidinium (2E)-but-2-ene-di-o-ate bis-[(2E)-but-2-enedioic acid]}, 2C12H19N2O+·C4H2O4 2-·2C4H4O4, has a single oxotremorine monocation protonated at the pyrrolidine nitro-gen, one fumaric acid mol-ecule and half of a fumarate dianion in the asymmetric unit. The ions and fumaric acid mol-ecules are held together by N-H⋯O and O-H-⋯O hydrogen bonds in 40-membered rings with graph-set notation R 6 6(40). The fumarate ions join these rings into infinite chains along [001].

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice.

4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and ß-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.

The methanol and ethanol solvates of 4-glutarato-N,N-diiso-propyl-tryptamine.

The solid-state structures of two solvated forms of 4-glutarato-N,N-diiso-propyl-tryptamine were determined by single-crystal X-ray diffraction, namely, 5-[(3-{2-[bis(propan-2-yl)azaniumyl]ethyl}-1H-indol-4-yl)oxy]-5-oxopentanoate meth-anol monosolvate, C21H30N2O4·CH3OH, and the analogous ethanol monosolvate, C21H30N2O4·C2H6O. In both compounds, the 4-glutarato-N,N-di-iso--pro-pyl-tryptamine exists as a zwitterion with a protonated tertiary ammonium and a deprotonated glutarato carboxyl-ate. The tryptamine zwitterions and alcohol solvates in both structures combine to produce near identical hydrogen-bonding networks, with N-H⋯O and O-H⋯O hydrogen bonds joining the mol-ecules together in two-dimensional networks parallel to the (100) plane.

The crystal structure of baeocystin.

The title compound, baeocystin or 4-phosphor-yloxy-N-methyl-tryptamine {systematic name: 3-[2-(methylazaniumyl)ethyl]-1H-indol-4-yl hydrogen phosphate}, C11H15N2O4P, has a single zwitterionic mol-ecule in the asymmetric unit. The mol-ecule has an intra-molecular N-H⋯O hydrogen bond between the ammonium cation and the hydro-phosphate anion. In the crystal, the mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds into a three-dimensional network.

Synthesis, Structural Characterization, and Pharmacological Activity of Novel Quaternary Salts of 4-Substituted Tryptamines.

Aeruginascin (4-phosphoryloxy-N,N,N-trimethyltryptammonium) is an analogue of psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) that has been identified in several species of psilocybin-containing mushrooms. Our team previously reported the synthesis, structural characterization, and biological activity of the putative metabolite of aeruginascin (4-hydroxy-N,N,N-trimethyltryptammonium; 4-HO-TMT) and its potential prodrug (4-acetoxy-N,N,N-trimethyltryptammonium; 4-AcO-TMT). Here, we report the synthesis, structural characterization, and pharmacological activity of several quaternary tryptammonium analogues of 4-HO-TMT and 4-AcO-TMT, namely, 4-hydroxy-N,N-dimethyl-N-ethyltryptammonium (4-HO-DMET), 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium (4-HO-DMPT), and 4-hydroxy-N,N-dimethyl-N-isopropyltryptammonium (4-HO-DMiPT), as well as their hypothesized prodrugs 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium (4-AcO-DMET), 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT), and 4-acetoxy-N,N-dimethyl-N-isopropyltryptammonium (4-AcO-DMiPT). Compounds were synthesized using established methods, and structures were characterized by single-crystal X-ray diffraction. Test compounds were screened for in vitro pharmacological activity at a variety of receptors and transporters to determine potential targets of action. None of the compounds exhibited measurable affinity for the serotonin 2A receptor (5-HT2A), but several analogues had low micromolar affinity (K i) for the serotonin 1D receptor (5-HT1D) and serotonin 2B receptor (5-HT2B), where they appeared to be weak partial agonists with low micromolar potencies. Importantly, 4-HO-DMET, 4-HO-DMPT, and 4-HO-DMiPT displayed sub-micromolar affinity for the serotonin transporter (SERT; 370-890 nM). The same 4-hydroxy analogues had low to sub-micromolar potencies (IC50) for inhibition of 5-HT uptake at SERT in transfected cells (3.3-12.3 µM) and rat brain tissue (0.31-3.5 µM). Overall, our results show that quaternary tryptammonium analogues do not target 5-HT2A sites, suggesting the compounds lack psychedelic-like subjective effects. However, certain 4-hydroxy quaternary tryptammonium analogues may provide novel templates for exploring structure-activity relationships for selective actions at SERT.

Genetic Survey of Psilocybe Natural Products.

Psilocybe magic mushrooms are best known for their main natural product, psilocybin, and its dephosphorylated congener, the psychedelic metabolite psilocin. Beyond tryptamines, the secondary metabolome of these fungi is poorly understood. The genomes of five species (P. azurescens, P. cubensis, P. cyanescens, P. mexicana, and P. serbica) were browsed to understand more profoundly common and species-specific metabolic capacities. The genomic analyses revealed a much greater and yet unexplored metabolic diversity than evident from parallel chemical analyses. P. cyanescens and P. mexicana were identified as aeruginascin producers. Lumichrome and verpacamide A were also detected as Psilocybe metabolites. The observations concerning the potential secondary metabolome of this fungal genus support pharmacological and toxicological efforts to find a rational basis for yet elusive phenomena, such as paralytic effects, attributed to consumption of some magic mushrooms.

Crystal structure of serotonin.

The title compound, serotonin or 5-hy-droxy-tryptamine (5-HT) [systematic name: 3-(2-amino-eth-yl)-1H-indol-5-ol], C10H12N2O, has one mol-ecule in the asymmetric unit. The conformation of the ethyl-amino side chain is gauche-gauche [Ca-Ca-Cm-Cm and Ca-Cm-Cm-N (a = aromatic, m = methyl-ene) torsion angles = -64.2 (3) and -61.9 (2)°, respectively]. In the crystal, the mol-ecules are linked into a three-dimensional network by N-H⋯O and O-H⋯N hydrogen bonds.

The crystalline forms of nine hydrochloride salts of substituted tryptamines.

The crystal structures of the hydrochloride salts of nine substituted tryptamines, namely, 1-methyltryptammonium chloride, C11H15N2+·Cl-, (1), 2-methyl-1-phenyltryptammonium chloride, C17H19N2+·Cl-, (2), 5-methoxytryptammonium chloride, C11H15N2O+·Cl-, (3), 5-bromotryptammonium chloride, C10H12BrN2+·Cl-, (4), 5-chlorotryptammonium chloride, C10H12ClN2+·Cl-, (5), 5-fluorotryptammonium chloride, C10H12FN2+·Cl-, (6), 5-methyltryptammonium chloride, C11H15N2+·Cl-, (7), 6-fluorotryptammonium chloride, C10H12FN2+·Cl-, (8), and 7-methyltryptammonium chloride, C11H15N2+·Cl-, (9), are reported. The seven tryptamines with N-H indoles, (3)-(9), show very similar structures, with N-H...Cl hydrogen-bonding networks forming two-dimensional sheets in the crystals. These sheets are combinations of R42(8) and R42(18) rings, and C21(4) and C21(9) chains. Substitution at the indole N atom reduces the dimensionality of the hydrogen-bonding network, with compounds (1) and (2) demonstrating one-dimensional chains that are a combination of different rings and parallel chains.

'Foxtrot' fumarate: a water-soluble salt of N,N-di-allyl-5-methoxytryptamine (5-MeO-DALT).

The title compound, bis-(N,N-diallyl-5-meth-oxy-tryptammonium) (5-MeO-DALT) fumarate (systematic name: bis-{N-[2-(5-meth-oxy-1H-indol-3-yl)eth-yl]- N-(prop-2-en-1-yl)prop-2-en-1-aminium} (E)-but-2-enedioate), 2C17H23N2O+·C4H2O4 2-, has a single tryptammonium cation and half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by a series of N-H⋯O hydrogen bonds. These chains are combinations of R 4 4(22) rings, and C 2 2(14) and C 4 4(28) parallel chains along [111].

5-Meth-oxy-N,N-di-n-propyl-tryptamine (5-MeO-DPT): freebase and fumarate.

The solid-state structures of the synthetic psychedelic 5-meth-oxy-N,N-di-n-propyl-tryptamine (5-MeO-DPT) {systematic name: N-[2-(5-meth-oxy-1H-indol-3-yl)eth-yl]-N-propyl-propan-1-amine}, C17H25N2O, and its fumarate salt, bis-(5-meth-oxy-N,N-di-n-propyl-tryptammonium) fumarate (systematic name: bis-{N-[2-(5-meth-oxy-1H-indol-3-yl)eth-yl]-N-propyl-propan-1-aminium} but-2-ene-dio-ate), 2C17H25N2O+·C4H2O4 2-, are reported. The freebase has a single tryptamine mol-ecule in the asymmetric unit. The mol-ecules are linked together by N-H⋯N hydrogen bonds in zigzag chains along the [010] direction. The fumarate salt has a single tryptammonium cation and half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by a series of N-H⋯O hydrogen bonds. These chains are combinations of R 4 4(22) rings, and C 2 2(14) and C 4 4(28) parallel chains along [001].

Psilacetin derivatives: fumarate salts of the meth-yl-ethyl, meth-yl-allyl and diallyl variants of the psilocin prodrug.

The solid-state structures of the salts of three psilacetin derivatives, namely, 4-acet-oxy-N-eth-yl-N-methyl-tryptammonium (4-AcO-MET) hydro-fumarate {sys-tematic name: [2-(4-acet-yloxy-1H-indol-3-yl)eth-yl](meth-yl)ethyl-aza-nium 3-carb-oxy-prop-2-enoate}, C15H21N2O2 +·C4H3O4 -, 4-acet-oxy-N-allyl-N-methyl-tryptammonium (4-AcO-MALT) hydro-fumarate {systematic name: [2-(4-acet-yl-oxy-1H-indol-3-yl)eth-yl](meth-yl)prop-2-enyl-aza-nium 3-carb-oxy-prop-2-eno-ate}, C16H21N2O2 +·C4H3O4 -, and 4-acet-oxy-N,N-di-allyl-tryptammonium (4-AcO-DALT) fumarate-fumaric acid (1/1) (systematic name: bis-{[2-(4-acet-yloxy-1H-indol-3-yl)eth-yl]diprop-2-enyl-aza-nium} but-2-enedioate-(E)-butenedioic acid (1/1)), 2C18H23N2O2 +·C4H2O4 2-·C4H4O4, are reported. All three salts possess a protonated tryptammonium cation. The 4-AcO-MET and 4-AcO-MALT compounds are charge-balanced by 3-carb-oxy-acrylate (hydro-fumarate) anions. The 4-AcO-DALT complex crystallizes as a two-to-one tryptammonium-to-fumarate salt, which co-crystallizes with a fumaric acid mol-ecule. Each structure is consolidated by N-H⋯O and O-H⋯O hydrogen bonds.

2,5-Di-methyl-bufo-tenine and 2,5-di-methyl-bufo-teni-dine: novel derivatives of natural tryptamines found in Bufo alvarius toads.

The solid-state structure of the bufotenine derivative bis-(5-meth-oxy-2,N,N-tri-methyl-tryptammonium) (5-MeO-2-Me-DMT) fumarate (systematic name: bis-{[2-(5-meth-oxy-2-methyl-1H-indol-3-yl)eth-yl]di-methyl-aza-nium} (2E)-but-2-enedioate), 2C14H21N2O+·C4H2O4 2-, the bufotenidine derivative 5-meth-oxy-2,N,N,N-tetra-methyl-tryptammonium (5-MeO-2-Me-TMT) iodide {systematic name: [2-(5-meth-oxy-2-methyl-1H-indol-3-yl)eth-yl]tri-methyl-aza-nium iodide}, C15H23N2O+·I-, and the hydrate of the same {systematic name: [2-(5-meth-oxy-2-methyl-1H-indol-3-yl)eth-yl]tri-methyl-aza-nium iodide monohydrate}, C15H23N2O+·I-·H2O, are reported. The structure of 5-MeO-2-Me-DMT fumarate possesses one tryptammonium cation and a half of a fumarate dianion in the asymmetric unit, linked together by N-H⋯O hydrogen bonds in infinite two-dimensional networks parallel to the (101) plane. The structure of 5-MeO-2-Me-TMT iodide possesses one tryptammonium cation and one iodide anion in the asymmetric unit. The ions are linked via N-H⋯I hydrogen bonds, and indoles are coupled in dimers through π-π inter-actions. The hydrate of 5-MeO-2-Me-TMT iodide possesses one tryptammonium cation, one iodide anion and one water mol-ecule in the asymmetric unit. It shows N-H⋯I and O-H⋯I hydrogen bonds that couple the tryptammonium cations into dimers.

Bufotenidinium iodide.

The title compound, 5-hy-droxy-N,N,N-tri-methyl-tryptammonium (5-HTQ) iodide {systematic name: [2-(5-hy-droxy-1H-indol-3-yl)eth-yl]tri-methyl-aza-nium iodide}, C13H19N2O+·I-, has a single tryptammonium cation and one iodide anion in the asymmetric unit. The ions are held together by N-H⋯I and O-H⋯I hydrogen bonds in infinite chains along [100].

DMT analogues: N-ethyl-N-propyl-tryptamine and N-allyl-N-methytryptamine as their hydro-fumarate salts.

The solid-state structures of the hydro-fumarate salts of two N,N-di-alkyl-tryptamines, namely N-ethyl-N-propyl-tryptammonium (EPT) hydro-fumarate {systematic name: [2-(1H-indol-3-yl)eth-yl](meth-yl)propyl-aza-nium 3-carb-oxy-prop-2-enoate}, C15H23N2 +·C4H3O4 -, and N-allyl-N-methyl-tryptammonium (MALT) hydro-fumarate {systematic name: [2-(1H-indol-3-yl)eth-yl](meth-yl)(prop-2-en-1-yl)aza-nium 3-carb-oxy-prop-2-enoate}, C14H19N2 +·C4H3O4 -, are reported. Both compounds possess a protonated tryptammonium cation, and a hydro-fumarate anion in the asymmetric unit. The ethyl group of the EPT cation is modeled as a two-component disorder with 50% occupancy for each component. In the extended structure, N-H⋯O and O-H⋯O hydrogen bonds generate infinite two-dimensional networks parallel to the (001) plane for both compounds.