- NITRATED PSILOCYBIN DERIVATIVES AND USE THEREOF FOR MODULATING 5-HT2A RECEPTOR AND FOR TREATING A PSYCHIATRIC DISORDER
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Disclosed are nitrated psilocybin compounds of formula (I), wherein at least one of R2, R4, R5, R6, or R7, is a nitro group, and wherein each non-nitrated R2, R5, R6, or R7, is a hydrogen atom, an alkyl, O-alkyl or O-aryl group, wherein R4 when it is not nitrated is a hydrogen atom, an alkyl, O-alkyl or O-aryl group, a hydroxy group, or a phosphate group, and wherein R3a, and R3b, are a hydrogen atom, an alkyl group, an aryl group, or an acyl group, pharmaceutical formulations containing the same. The nitrated psilocybin compounds of formula (I) may be chemically synthesized or biochemically synthesized in host cells. The nitrated compounds of formula (I) may be used for modulating 5-HT2A receptor, and for treating a psychiatric disorder in a subject.
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- MITRAGYNINE ALKALOIDS AS OPIOID RECEPTOR MODULATORS
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The present invention provides a compound having the structure: or a pharmaceutically acceptable salt or ester thereof, and a method of treating a subject afflicted with pain, a depressive disorder, a mood disorder or an anxiety disorder by administering the compound to the subject.
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- Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators
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Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.
- Kruegel, Andrew C.,Gassaway, Madalee M.,Kapoor, Abhijeet,Váradi, András,Majumdar, Susruta,Filizola, Marta,Javitch, Jonathan A.,Sames, Dalibor
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p. 6754 - 6764
(2016/06/14)
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- N-(2-ARYLETHYL) BENZYLAMINES AS ANTAGONISTS OF THE 5-HT6 RECEPTOR
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The present invention relates to the use compounds of formula I which are antagonists of the 5-HT 6 receptor, for treating a cognitive disorder selected from the group consisting of age-related cognitive decline, mild cognitive impairment and dementia
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- Alpha-ethyltryptamines as dual dopamine-serotonin releasers
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The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT2Areceptor. The unique combination of dual DA/5-HT releasing activity and 5-HT2Areceptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential.
- Blough, Bruce E.,Landavazo, Antonio,Partilla, John S.,Decker, Ann M.,Page, Kevin M.,Baumann, Michael H.,Rothman, Richard B.
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p. 4754 - 4758
(2015/01/09)
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- Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet-Spengler reaction
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The pharmacologically interesting indole alkaloids (-)-mitragynine, (+)-paynantheine and (+)-speciogynine were synthesised in nine steps from 4-methoxytryptamine by a route featuring (i) an enantioselective thiourea-catalysed Pictet-Spengler reaction, providing the tetrahydro-β- carboline ring and (ii) a Pd-catalysed Tsuji-Trost allylic alkylation, closing the D-ring. The Royal Society of Chemistry 2012..
- Kerschgens, Isabel P.,Claveau, Elise,Wanner, Martin J.,Ingemann, Steen,Van Maarseveen, Jan H.,Hiemstra, Henk
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p. 12243 - 12245
(2013/01/16)
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- Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors
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Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.
- Cuny, Gregory D.,Ulyanova, Natalia P.,Patnaik, Debasis,Liu, Ji-Feng,Lin, Xiangjie,Auerbach, Ken,Ray, Soumya S.,Xian, Jun,Glicksman, Marcie A.,Stein, Ross L.,Higgins, Jonathan M.G.
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scheme or table
p. 2015 - 2019
(2012/04/05)
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- Palladium-catalyzed synthesis of tryptamines and tryptamine homologues: synthesis of psilocin
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A new Pd-catalyzed method for the synthesis of tryptamines is developed, and its applications to the synthesis of Corey's aspidophytine tryptamine 15 and psilocin 20 are also described.
- Hu, Chunmei,Qin, Hua,Cui, Yuxin,Jia, Yanxing
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experimental part
p. 9075 - 9080
(2010/01/16)
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- Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine d3 and serotonin 5-HT 1A and 5-HT2A receptors: Design, synthesis, and effects on behavior
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Dopamine D3 antagonism combined with serotonin 5-HT1A and 5-HT2A receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for
- Butini, Stefania,Gemma, Sandra,Campiani, Giuseppe,Franceschini, Silvia,Trotta, Francesco,Borriello, Marianna,Ceres, Nicoletta,Ros, Sindu,Coccone, Salvatore Sanna,Bernetti, Matteo,De Angelis, Meri,Brindisi, Margherita,Nacci, Vito,Fiorini, Isabella,Novellino, Ettore,Cagnotto, Alfredo,Mennini, Tiziana,Sandager-Nielsen, Karin,Andreasen, Jesper Tobias,Scheel-Kruger, Jorgen,Mikkelsen, Jens D.,Fattorusso, Caterina
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supporting information; experimental part
p. 151 - 169
(2009/09/25)
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- Novel Aryl Piperazine Derivatives With Medical Utility
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This invention provides novel aryl piperazine derivatives having medical utility, in particular as modulators of dopamine and serotonin receptors, preferably the D3, D2-like and 5-HT2 receptor subtypes, and in particular u
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Page/Page column 28; 21
(2009/10/01)
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- New synthetic technologies for the construction of heterocycles and tryptamines
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New synthetic methods for the construction of novel heterocycles and tryptamines are described. Thus, N-Boc anilines (I) are sequentially converted to heterocycles II ((3-(2-aminophenyl)pyrrolidin-3-ol) derivatives),III (substituted 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrol idines), and VI (2-(4,5-dihydro-1H-pyrrol-3-yl)aniline) derivatives through a route involving t-BuLi induced ortho-metalation/ LaCl3 2LiCl metalexchange, reaction with N-Boc pyrrolidin-3-one (5), and subsequent deca rboxylative fragmentation. Labile intermediates VI are effectively converted to tryptamines Xa and Xb under controlled proticacidconditions.Inadditiontoprovidingexpedientaccesstothe2-oxo- 1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines (III), the method is applicable to the synthesis of the corresponding 2-oxo-1,2-dihydrospirobenzo[d] [1,3]oxazine-4,3'-piperidine series of spirocycles (e.g., 42) and their precursors (3-(2-aminophenyl)piperidin-3-ol derivatives, e.g., 43) by using N-Boc-protected piperidin-3-one (40). Applications of the developed synthetic technologies to the synthesis of regioisomeric spirocycles 87 and 90, tryptamines 88 and 91, Corey's aspidophytine tryptamine (97), and efavirenz (1) are also described.
- Nicolaou, K. C.,Krasovskiy, Arkady,Majumder, Utpal,Trepanier, Vincent E.,Chen, David Y.-K.
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supporting information; experimental part
p. 3690 - 3699
(2009/09/24)
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- An expedient strategy for the synthesis of tryptamines and other heterocycles
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(Chemical Equation Presented) Making many from one: N-Boc-protected anilines are converted into an array of useful N-heterocycles and tryptamines through an expedient, cascade-based synthetic sequence involving ortho metalation and subsequent coupling wit
- Nicolaou,Krasovskiy, Arkady,Trepanier, Vincent E.,Chen, David Y.-K.
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supporting information; experimental part
p. 4217 - 4220
(2009/03/12)
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- Novel tetrahydro-β-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)
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A structure-activity relationship study was conducted on a series of tetrahydro-β-carboline-1-carboxylic acid analogs in order to identify the key functionality responsible for activity against the mitogen-activated protein kinase-activated protein kinase 2 enzyme (MK-2). The compounds were further evaluated for their ability to inhibit TNFα production in U937 cells and in vivo. These compounds represent a novel structural class of compounds capable of inhibiting MK-2 with remarkable selectivity.
- Trujillo, John I.,Meyers, Marvin J.,Anderson, David R.,Hegde, Shridhar,Mahoney, Matthew W.,Vernier, William F.,Buchler, Ingrid P.,Wu, Kun K.,Yang, Syaluan,Hartmann, Susan J.,Reitz, David B.
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p. 4657 - 4663
(2008/02/13)
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- Discovery of a novel and potent human and rat β3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl] -1H-indol-7-yloxy]acetic acid
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In search for potent and selective β3-adrenergic receptor (β3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human β1-, β2-, and β3-ARs and rat β3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' β3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among β3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human β3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good β3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human β3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H- indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human β3-AR agonistic activity (EC50 = 0.062 nM, IA = 116%) with 210- and 103-fold selectivity over human β2-AR and β1-AR, respectively. Compound 96 also exhibited potent rat β3-AR agonistic activity (EC50 = 0.016 nM, IA = 110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.
- Harada, Hiroshi,Hirokawa, Yoshimi,Suzuki, Kenji,Hiyama, Yoichi,Oue, Mayumi,Kawashima, Hitoshi,Kato, Hiroshi,Yoshida, Naoyuki,Furutani, Yasuji,Kato, Shiro
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p. 184 - 198
(2007/10/03)
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- Melatonin receptor ligands: Synthesis of new melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study
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The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C: N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.
- Mor, Marco,Rivara, Silvia,Silva, Claudia,Bordi, Fabrizio,Plazzi, Pier Vincenzo,Spadoni, Gilberto,Diamantini, Giuseppe,Balsamini, Cesarino,Tarzia, Giorgio,Fraschini, Franco,Lucini, Valeria,Nonno, Romolo,Stankov, Bojidar Michaylov
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p. 3831 - 3844
(2007/10/03)
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- STRUCTURAL DETERMINATION OF A NATURAL ALKALOID, 5-METHOXY-1-OXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE AND THE SYNTHESIS OF THE CORRESPONDING 8-METHOXY COMPOUND
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Structure of a natural alkaloid, 5-methoxy-1-oxo-1,2,3,4-tetrahydro-β-carboline, was determined unequivocally by synthesis and the reported spectral data were found to be revised in some points.
- Yamada, Fumio,Saida, Yoshihiro,Somei, Masanori
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p. 2619 - 2627
(2007/10/02)
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- Psychotomimetic N-Methyl-N-isopropyltryptamines. Effects of Variation of Aromatic Oxygen Substituents
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Eight N-methyl-N-isopropyltryptamines (MIPTs) possessing various aromatic oxygen substituents were prepared, characterized, and evaluated for hallucinogenic activity in man.In at least two instances (the Ar H and the Ar 5-OCH3, 1 and 4) the unsymmetrical nitrogen substitution led to a substantial increase in potency as well as oral activity when compared to the symmetrical dimethyl homologues.Qualitatively, 4-hydroxy-N-methyl-N-isopropyltryptamine (2) was the most interesting in overall effect, producing a classic hallucinogenic profile.The 5-methoxy congeger 4 resulted in a state characterized by heightened conceptual stimulation lacking in visual phenomena.Other members of the series exhibited diminished effects.
- Repke, David B.,Grotjahn, Douglas B.,Shulgin, Alexander T.
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p. 892 - 896
(2007/10/02)
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