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Key Word Index - Virola sebifera; Myristicaceae; hallucinogenic plant; alkaloids; N-methyl-N-acetyltryptamine; N-methyl-N-formyltryptamine; 2-methyl-1,2,3,4-tetrahydro-β-carboline; N,N-dimethyltryptamine; N,N-dimethyltryptamine-N-oxide; N-monomethyltryptamine. - Bark of Virola sebifera used in the preparation of hallucinogenic snuffs and drinks in Venezuela has yielded N-methyl-N-formyltryptamine and N-methyl-N-acetyltryptamine, which exist in two rotameric forms reflecting hindered rotation around the carbon-nitrogen bond of the amide function.They were detected by HPLC as well as NMR. 2-Methyl-1,2,3,4-tetrahydro-β-carboline, N,N-dimethyltryptamine, its oxide and N-monomethyltryptamine were also identified.

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Non peptide products have been found to show nanomolar binding and functional affinities at the human tachykinin NK-2 receptor. The new antagonists do not possess stereogenic centers and their thermal behaviour in solution is featured by a peculiar set of conformational stereoisomers. A macroscopic viewpoint is preferentially adopted to rationalize the obtained results.

Ayahuasca is an Amazonian plant beverage obtained by infusing the pounded stems of Banisteriopsis caapi in combination with the leaves of Psychotria viridis. P. viridis contains the psychedelic indole N,N-dimethyltryptamine (DMT). This association has a wide range of use in religious rituals around the world. In the present work, an easy, fast and non-destructive method by Nuclear Magnetic Resonance of proton (1H NMR) for quantification of DMT in ayahuasca samples was developed and validated. 2,5-Dimethoxybenzaldehyde (DMBO) was used as internal standard (IS). For this purpose, the area ratios produced by protons of DMT (N(CH3)2) at 2.70 ppm, singlet, (6H) and for DMBO (Ar(OCH3)2) at 3.80 and 3.89 ppm, doublet, (6H) were used for quantification. The lower limit of quantification (LLOQ) was 12.5 μg/mL and a good intra-assay precision was also obtained (relative standard deviation 1H NMR method is not time consuming and can be readily applied to monitor this tryptamine in plant preparations. We believe that qNMR can be used for identification and quantification of many plant-based products and metabolites with important advantages, while comparing with other analytical techniques.

The present invention relates to compositions comprising N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and/or partially deuterated N,N-dimethyltryptamine. In particular, the present invention relates to compositions comprising a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more deuterated N,N- dimethyltryptamine compound selected from α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine. Additional and alternative compositions of the present invention comprise a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more partially deuterated N,N-dimethyltryptamine compound selected from α,β,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N- dimethyltryptamine, and α-deutero-N,N-dimethyltryptamine. Methods of synthesising compositions of the present invention, and methods of use of presently described compositions in treating psychiatric or psychocognitive disorders, such as major depressive disorder, are also provided.

Herein, we presented Ru-SNS complex that serves as a useful catalyst for C-3 alkylation of 1H-indoles with various aliphatic primary and secondary alcohols including cyclic alcohols as well as benzylic alcohols. The selective synthesis of bisindolylmethane derivatives is also achieved from the same set of indole and alcohol just by altering the reaction parameters. Furthermore, the sustainable synthesis of C-3 alkylated indoles directly from 2-(2-nitrophenyl)ethan-1-ol and alcohols catalysed by a Ru-complex via “borrowing hydrogen” strategy is reported. This protocol provides an atom-economical sustainable route to access structurally important compounds like arundine, vibrindole A and tryptamine based derivatives. (Figure presented.).

The invention provides indole derivatives or stereisomers, tautomers, nitrogen oxides, solvate, metabolic products, pharmaceutically acceptable salts or prodrugs thereof for treating the alzheimer disease. The invention further discloses a pharmaceutical composition containing the compounds and a method of using the compounds or the pharmaceutical composition thereof to treat the alzheimer disease.

An iron(0) complex bearing a cyclopentadienone ligand catalyzed N-methylation and N-ethylation of aryl and aliphatic amines with methanol or ethanol in mild and basic conditions through a hydrogen autotransfer borrowing process is reported. A broad range of aromatic and aliphatic amines underwent mono- or dimethylation in high yields. DFT calculations suggest molecular hydrogen acts not only as a reducing agent but also as an additive to displace thermodynamic equilibria.

A practical and scalable single electron transfer reduction mediated by sodium dispersions has been developed for the reduction and reductive deuteration of tertiary amides. The chemoselectivity of this method highly depends on the nature of the proton donor. The challenging reduction via C-N bond cleavage has been achieved using Na/EtOH, affording alcohol products, while the use of Na/NaOH/H2O leads to the formation of amines via selective C-O scission. Sodium dispersions with high specific surface areas are crucial to obtain high yields and good chemoselectivity. This new method tolerates a range of tertiary amides. Moreover, the corresponding reductive deuterations mediated by Na/EtOD-d1 and Na/NaOH/D2O afford useful α,α-dideuterio alcohols and α,α-dideuterio amines with an excellent deuterium content.

Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (Ki) of 29 and 19 μM respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

The present invention provides a class of non-nucleoside anti-viral inhibitors, in particular to such as shown in formula I benzo heterocyclic compound or its pharmaceutically acceptable salt or hydrate, the invention also provides the compound or its pharmaceutically acceptable salt or hydrate of the preparation method. Pharmacological test indicates that the compound or its pharmaceutically acceptable salt or hydrate can effectively inhibit hepatitis b virus DNA replication and hepatitis c virus RNA replication, therefore, the invention also provides the compounds in the preparation of preventing and/or the treatment of viral infections, particularly hepatitis b virus (HBV) infection, hepatitis c virus (HCV) infection of use of the medicament. (by machine translation)

Treatment of o-nitrostyrenes with aqueous TiCl3 solution at room temperature afforded indoles through a formal reductive C(sp2)-H amination process. A range of functions such as halides (Cl, Br), carbonyl (ester, carbamate), cyano, hydroxy, and amino groups were tolerated. From β,β-disubstituted o-nitrostyrenes, 2,3-disubstituted indoles were formed by a domino reduction/cyclization/migration process. Mild conditions, simple experimental procedure, ready accessibility of the starting materials and good to excellent yields characterize the present transformation. The methodology was used as a key step in a concise synthesis of rizatriptan and a formal total synthesis of aspidospermidine. Mild and efficient treatment of o-nitrostyrenes with aqueous TiCl3 solution at room temperature afforded indoles through a formal reductive C(sp2)-Hamination process. A concise synthesis of a marketed drug (rizatriptan) and a formal total synthesis of aspidospermidine featuring this novel N-heterocyclization process are reported.

The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.

Indolethylamine-N-methyltransferase (INMT) is a Class 1 transmethylation enzyme known for its production of N,N-dimethyltryptamine (DMT), a hallucinogen with affinity for various serotonergic, adrenergic, histaminergic, dopaminergic, and sigma-1 receptors. DMT is produced via the action of INMT on the endogenous substrates tryptamine and S-adenosyl-l-methionine (SAM). The biological, biochemical, and selective small molecule regulation of INMT enzyme activity remain largely unknown. Kinetic mechanisms for inhibition of rabbit lung INMT (rabINMT) by the product, DMT, and by a new novel tryptamine derivative were determined. After Michaelis-Menten and Lineweaver-Burk analyses had been applied to study inhibition, DMT was found to be a mixed competitive and noncompetitive inhibitor when measured against tryptamine. The novel tryptamine derivative, N-[2-(1H-indol-3-yl)ethyl]-N′,N′-dimethylpropane-1,3-diamine (propyl dimethyl amino tryptamine or PDAT), was shown to inhibit rabINMT by a pure noncompetitive mechanism when measured against tryptamine with a Ki of 84 μM. No inhibition by PDAT was observed at 2 mM when it was tested against structurally similar Class 1 methyltransferases, such as human phenylethanolamine-N-methyltransferase (hPNMT) and human nicotinamide-N- methyltransferase (hNNMT), indicating selectivity for INMT. The demonstration of noncompetitive mechanisms for INMT inhibition implies the presence of an inhibitory allosteric site. In silico analyses using the computer modeling software Autodock and the rabINMT sequence threaded onto the human INMT (hINMT) structure (Protein Data Bank entry 2A14) identified an N-terminal helix-loop-helix non-active site binding region of the enzyme. The energies for binding of DMT and PDAT to this region of rabINMT, as determined by Autodock, were ～6.34 and ～7.58 kcal/mol, respectively. Assessment of the allosteric control of INMT may illuminate new biochemical pathway(s) underlying the biology of INMT.

In this study, a novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indoles (8) is presented starting from (1H-1,2,4-triazol-1-yl)methanol (5) and indolines (6) under 98% H 2SO4 at room temperature for 4-24 h, followed by deacetylation and dehydrogenation. Based on this finding, a novel route to synthesize Rizatriptan starting from tryptamine was designed and accomplished with 48.5% overall yield in 6 steps. Compared with operational art, the new route afforded higher yield and more pure products requiring no chromatographic purification, which may further be applied in industrialization.

Provided herein are methods and compositions inter alia for treating diseases, including hyperproliferative diseases, migraine headaches, and depression.

Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurological disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed.

5-Hydroxytryptamine 6 receptors (5-HT6R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structureactivity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT6 receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT6R with the Ki of 23.4 and 20.5nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze.

A series of tryptamine derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. The preliminary SAR was discussed. Compounds 2e and 4a showed potent antiviral activity (IC50 = 0.4 and 50 = 40.6 and >25 μM, respectively).

The invention provides compounds of formula I and compositions thereof. The invention further provides methods of using the compounds and compositions. The compounds of the invention can provide high affinity binding to sigma-1 receptors in a mammal. The compounds can exhibit selectivity for the sigma-1 receptor over the sigma-2 receptor. The compounds and compositions of the invention can also be used to treat conditions that involve the sigma-1 receptor, such as addiction, cardiovascular conditions, and cancer, for example, cancer of the breast, lung, prostate, ovarian, colorectal, or the CNS.

Molecular modeling and structure-activity relationship studies were performed to propose a model for binding of the neurotransmitter serotonin (5-HT) to the human serotonin transporter (hSERT). Homology models were constructed using the crystal structure of a bacterial homologue, the leucine transporter from Aquifex aeolicus, as the template and three slightly different sequence alignments. Induced fit docking of 5-HT into hSERT homology models resulted in two different binding modes. Both show a salt bridge between Asp98 and the charged primary amine of 5-HT, and both have the 5-HT C6 position of the indole ring pointing toward Ala173. The difference between the two orientations of 5-HT is an enantiofacial discrimination of the indole ring, resulting in the 5-hydroxyl group of 5-HT being vicinal to either Ser438/Thr439 or Ala169/Ile172/Ala173. To assess the binding experimentally, binding affinities for 5-HT and 17 analogues toward wild type and 13 single point mutants of hSERT were measured using an approach termed paired mutant-ligand analogue complementation (PaMLAC). The proposed ligand-protein interaction was systematically examined by disrupting it through site-directed mutagenesis and reestablishing another interaction via a ligand analogue matching the mutated residue, thereby minimizing the risk of identifying indirect effects. The interactions between Asp98 and the primary amine of 5-HT and the interaction between the C6-position of 5-HT and hSERT position 173 was confirmed using PaMLAC. The measured binding affinities of various mutants and 5-HT analogues allowed for a distinction between the two proposed binding modes of 5-HT and biochemically support the model for 5-HT binding in hSERT where the 5-hydroxyl group is in close proximity to Thr439.

We report novel iridium(III)-catalyzed reactions that afford substituted indoles via the indirect functionalization of alcohols via C-3 selective alkylation of indoles with alcohols and a one-pot cascade strategy from amino- or nitro-phenyl ethyl alcohols, which incorporates oxidative cyclization and C-3 alkylation.

The sequence of hydroformylation and Fischer indole synthesis starting from amino olefins and aryl hydrazines is described. In a convergent manner, the two units bearing pharmacologically relevant substituents are assembled in the final indolization step. This modular and diversity-oriented approach to tryptamines and homotryptamines can be conducted in water and allows synthesis of branched and nonbranched tryptamines as well as tryptamine-based pharmaceuticals such as the 5-HT1D agonist L 775 606.

(matrix presented) Various tryptamines are captured by a vinylsulfonylmethyl polystyrene resin, generating a safety-catch linkage. β-Carbolines can be formed from 4 by a Pictet-Spengler reaction with the introduction of R1. Tryptamine 4 can also be derivatized by acylation or copper-mediated coupling to introduce R2. If X = Br, Suzuki coupling can be used to introduce R3. After derivatization, the indole derivatives are activated with methyl iodide and released under mild basic condition.

The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.

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Simple syntheses of serotonin (1a), N-methylserotonin (1b), bufotenine (1c), and melatonin (2), and the first total synthesis of N-(indol-3-yl)methyl-N-methyl-5-methoxytryptamine (3) from tryptamine (4a) are reported through acid catalyzed nucleophilic substitution reaction of 1-hydroxytryptamines.

The synthesis and spectral properties of new radioiodinated indolealkylamines like 2-[131 I]-iodo-N,N-dimethyltryptamine, 2-[131 I]-iodo-N-methyltryptamine, 2-[131 I]-iodo-5-methoxy-N,N-dimethyltryptamine, 2-[131 I]-iodo-5-hydroxy-N,N-dimethyltryptamine (2-[131 I]-iodo-bufotenine), and 2-[131I]-iodo-tryptamine and the known 2-[131I]-iodo-N-acetyl-5-methoxy-tryptamine (2-[131I]-iodo-melatonine) are described herein. These were synthesized by a high-yield novel method, and their spectral properties are fully described. These compounds are of biological importance and can be used for brain mapping with SPECT technology.

Various types of 1-hydroxyindoles were prepared for the first time.Through methylation or acid catalyzed nucleophilic bromination of N,N-dimethyl-1-hydroxytryptamine, simple syntheses of lespedamine and 5-bromo-N,N-dimethyltryptamine were achieved, respectively.

A class of substituted imidazole, triazole and tetrazole derivatives are selective agonists of 5-HT 1 -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated.

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1,3-Dinitro-2-(indol-3'-yl)-propanes 3 are synthesized by Michael reaction of nitromethane with the indolylnitroethenes 2. - Reaction of the aldehydes 4 and 10 with the benzylamines 12 as well as the reaction of the indolylalkylamines 6a and 9a with the benzaldehydes 11 lead to Schiff bases which are reduced to N-benzyl-(indol-3-ylmethyl)-amines 13 and N-benzyl-(indol-3-ylethyl)-amines 14, respectively; tert amines 16 are synthesized via the formamides 15, amines 18 are prepared according to Mannich. - Inhibitory effects on Mycobacterium tuberculosis H 37 Ra are investigated, a structure-activity relationship is discussed.

The present invention provides a method of inhibiting gastric acid secretion in mammals by administering a 5-HT1A agonist compound or a pharmaceutically acceptable salt thereof.

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