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.

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.

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.