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A catalytic asymmetric Pictet-Spengler reaction has been developed, wherein treating substituted tryptamines with an aldehyde in the presence of a catalytic amount of a chiral phosphoric acid provides the corresponding tetrahydro-beta-carboline derivatives in high yields and enantiomeric excesses. The reaction works well with both aliphatic and aromatic aldehydes.
A novel series of 5-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)tryptamines was designed, synthesized, and evaluated as 5-HT1D receptor agonists. Compounds such as 8d,f,k were identified which had comparable affinity, potency, and receptor selectivity to that of the antimigraine drug sumatriptan. Both 8d,k were found to be well absorbed in the rat with oral bioavailabilities of 66% and 62%, respectively. Additionally, 8d was found to be selective over other non-serotonergic receptors and exhibited relatively low central nervous system penetration.
A series of derivatives of 4-aminophenethylamine was synthesized and their effect on monoamine oxidase (MAO) activity in the brain was evaluated. Several of the new compounds were potent and selective inhibitors of the A form of MAO but were poor inhibitors of the B form. The most active compounds were the 2,6-dichloro-(9) and the 2-halogeno-4-dimethylaminophenethylamines (5, 6, and 8). Some of the compounds also strongly antagonized aggressive behavior in isolated male mice. This effect was correlated to the MAO inhibition when tyramine was used as substrate. Significant correlations between MAO inhibition in vivo and potentiation of the syndromes produced by 5-hydroxytryptophan and tryptamine and antagonism of reserpine sedation were obtained.
The photoelectron spectrum of lysergic acid diethylamide (LSD) reveals five ionization potentials (IP's) between 7.25 and 9.75 eV arising from the aromatic (pi) portion of the molecule and IP's of 8.4 eV arising from the tertiary amine and 8.5-9.0 and 9.1 eV arising from the amide group. Comparisons of the IP's of LSD, and of phenethylamines and tryptamines reported by us elsewhere, with activities of these compounds in rat and human behavioral tests show that increasing activity is paralleled by decreasing IP.
The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 micromol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4, 5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds.
Tryptamines disubstituted at the beta-position with fluorine have been synthesized as part of our research program to study the effects of fluorine substitution on the biological activities of neuroactive amines. Treatment of N-Boc-3-azidoacetyl indoles, prepared from readily available 2-chloracetylindoles, with dimethoxyethylamino sulfurtrifluoride produced the corresponding 3-(2-azido-1,1-difluoroethyl)indoles. Reduction of the azide to amine with hydrogen over Pd-C and careful removal of the N-Boc protecting group produced beta,beta-difluorotryptamines.
The coupling reaction of tetraacetylsecologanin with 2,3-dihydro-2-oxotryptamine and its N(b)-benzyl derivative was investigated. With the benzylated amine, the reaction was stopped at the tetracyclic ester level, and with the unsubstituted amine it was immediately followed by lactamization. In both cases, the products were formed with high stereoselectivity at C-3, but as an epimeric pair of 7R and 7S in a ratio of 1:3. The bulky benzyl substituent at N-4 directed the stereoselectivity at C-3 in favor of the S configuration. In the nonbenzylated compounds, the reversible coupling reaction is probably nonstereoselective, but in lactamization the 3R epimer is sterically favored and faster and gives the final lactam in this configuration. The formation of the spiro compounds may serve as a model reaction in the interpretation of the stereoselectivity of the coupling reaction of secologanin with tryptamine in the presence of strictosidine synthase.
1,2-Bis(1H-indol-3-yl)ethane-1,2-dione (1), a bisindole alkaloid, was isolated from the marine sponge Smenospongia sp. The known compounds indole-3-carbaldehyde (2), 6-bromoindole-3-carbaldehyde (3), and tryptamine (4) and mixtures of the (Z/E) isomers of 6-bromo-2'-demethylaplysinopsin (5a/5b) and 6-bromo-3'-deimino-2',4'-bis(demethyl)-3'-oxoaplysinopsin (6a/6b) were also isolated.
A beta-carboline-, a tryptamine-, and two phenylethylamine-derived alkaloids and three known aromatic compounds were isolated from the aerial parts and roots of Cyathobasis fruticulosa (Bunge) Aellen, and their structures were elucidated by spectroscopic techniques. The one new alkaloid, N-methyl-N-formyl-4-hydroxy-beta-phenylethylamine (1), showed marginal antifungal activity.
[reaction: see text] Starting from tryptamine 4 and isatin 5, a biomimetic approach to the pentacyclic substructure 1 of perophoramidine and communesin was developed. The key steps were to create a stable three/six bicyclic system 2 on the 2,3-double bond of an indole derivative 3 by an intramolecular cyclopropanation, followed by ring opening of the resulting cyclopropane ring with the in situ generated amine group of an aniline.
Melatonin's O-methyl and N-acetyl residues are not only the basis of its amphilicity enabling the molecule to enter all organs and all subcellular compartments, but are also decisive for its antioxidant properties. We have compared melatonin's redox chemistry with that of several structural analogs: tryptamine, N-acetyltryptamine, serotonin, N-acetylserotonin, 5-methoxytryptamine, 6-chloromelatonin and 2-iodomelatonin. Scavenging of hydroxyl radicals (*OH) was measured in a scavenger competition assay based on ABTS cation radical (ABTS(*)+) formation. The capability of undergoing single-electron transfer reactions was studied using an ABTS(*)+ reduction assay, reflecting the more general property of scavenging organic cation radicals. Direct scavenging of superoxide anions (O2(*)-), under non-catalyzed conditions, was investigated in a hematoxylin autoxidation assay. Measurements of chemiluminescence were used for studying scavenging of O2(*)- under catalyzed conditions, either by hemin-mediated interaction or by combination with the respective indolyl cation radicals. Light emission was determined in the absence or presence of the *OH scavenger dimethylsulfoxide and the O2(*)- scavenger Tiron. Products formed by oxidation of the respective indoles in a moderately alkaline, hemin-catalyzed H2O2 system were analyzed by thin-layer chromatography and fluorometry. Absence of either the O-methyl or the N-acetyl residue causes marked diminutions in the capacities of scavenging *OH and ABTS(*)+ as well as in chemiluminescence emitted during oxidation. The importance of the N-acetyl group is insofar remarkable as it seems, at first glance, to be isolated from the indolic moiety; interactions between side chain and indolic moiety are therefore decisive for melatonin's redox properties. The 5-hydroxylated compounds are not generally more efficient scavengers, but particularly better reducers of ABTS(*)+; in the alkaline H2O2 system generating *OH and O2(*)-, melatonin was much more rapidly oxidized than the 5-hydroxylated and non-substituted analogs. Oxidative products formed from any of the compounds studied contained much less of substituted kynuramines as in the case of melatonin, indicating that radical chain termination by O2(*)- is considerably more efficient with melatonin. These findings are supported by measurements of chemiluminescence, which largely reflects pyrrole ring cleavage as a result of combination with superoxide anions. In this regard, only 6-chloromelatonin equalled melatonin, whereas the efficiency of 2-iodomelatonin was much lower, another indication for the importance of 2,3-dioxygenation.
Consistent with a serotonergic-midbrain raphe model of tonic immobility, four experiments designed to affect changes in serum tryptophan produced reliable effects on the duration of the response in chickens. Systemic injections of tryptophan, the dietary precursor to serotonin, led to a dose-dependent increase in immobility, with optimal effects being observed within 30 min after injection. Dietary depletion of endogenous tryptophan served to attenuate the duration of immobility, and a diet completely free of tryptophan, but supplemented with niacin, practically abolished the reaction. Dietary replacement served to reinstate the response. In a fifth experiment, tryptamine, an alternative metabolic by-product of tryptophan, was found to have no effect on immobility. The data are discussed in light of evidence showing serotonergic involvement in tonic immobility.
The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.
NIH3T3 fibroblast cells transfected with the full-length coding region of the MT2 human melatonin receptor stably expressed the receptor that is coupled to a pertussis toxin-sensitive G protein and exhibits high affinity for melatonin (K(I) = 261 pM). The order of apparent affinity for selected compounds was: 4-phenyl-2-propionamidotetralin (4P-PDOT) > 2-phenylmelatonin > 2-iodomelatonin > 2-bromomelatonin > 6-chloromelatonin > or = melatonin > luzindole > N-acetyl-tryptamine > or = N-[(2-phenyl-1H-indol-3-yl)ethyl]cyclobutanecarboxamide (compound 6) > N-acetylserotonin. 4P-PDOT exhibited a very high selectivity (approximately 22,000 times) for the MT2 receptor with respect to the mt1 receptor subtype, as tested in comparative experiments with membrane preparations from NIH3T3 cells stably transfected with the human mt1 receptor. MT2 melatonin receptors mediated incorporation of [35S]-GTPgammaS into isolated membranes via receptor catalyzed exchange of [35S]-GTPgammaS for GDP. The relative intrinsic activity and potency of the compounds were subsequently studied by using [35S]-GTPgammaS incorporation. The order of potency was equal to the order of apparent affinity. Melatonin and full agonists increased [35S]-GTPgammaS binding by 250% over basal (taken as 100%). Luzindole did not increase basal [35S]-GTPgammaS binding but competitively inhibited melatonin-stimulated [35S]-GTPgammaS binding, thus exhibiting antagonist action. The other two mt1 antagonists used here, 4P-PDOT and N-[(2-phenyl-1H-indol-3-yl)ethyl]cyclobutanecarboxamide, behaved as partial agonists at the MT2 subtype, with relative intrinsic activities of 0.37 and 0.39, respectively. These findings show, for the first time, important differences in the intrinsic activity of analogues between the human mt1 and MT2 melatonin receptor subtypes.
This review covers simple indole alkaloids, isoprenoid tryptamines, and bisindole alkaloids with a nonrearranged monoterpenoid unit. Newly isolated alkaloids, structure determinations, total syntheses and biological activities are reported. The literature from January to December 2000 is reviewed, and 182 references are cited.
We present the design, synthesis, and biological activity of three classes of tryptamine derivatives, which are non-planar analogues of the toxic anti-cancer agent fascaplysin. We show these compounds to be selective inhibitors of CDK4 over CDK2, the most active compound has an IC50 for the inhibition of CDK4 of 6 microM.
Tryptophan, tryptamine and peptides containing N-terminal tryptophan give two highly fluorescent products on treatment with dithiothreitol and acid ninhydrin reagent 1 or 2. The first fluorescent product (product A) gives an emission at 500nm on activation at 390-400nm and is stable for 20min. The second product (product B), which gives an emission at 530nm on activation at 470nm, is detectable within 1h after the reaction. It gives almost maximum intensity in 4h and is stable for at least 48h. Except lysine, which in equimolar amounts gives less than 1% of a product similar to product B, no other naturally occurring amino compounds give fluorescent products. A procedure is given for the determination of 0.05-34nmol of tryptophan in tissue extracts. By using this procedure rat brain was found to contain 17.56+/-0.76 (s.e.m.) nmol/g wet wt.
Pyridoxal kinase was purified 4760-fold from rat liver. The Km values for pyridoxine and pyridoxal were 120 and 190 microM respectively, and pyridoxine showed substrate inhibition at above 200 microM. Pyridoxamine 5-phosphate oxidase was also purified 2030-fold from rat liver, and its Km values for pyridoxine 5-phosphate and pyridoxamine 5-phosphate were 0.92 and 1.0 microM respectively. Pyridoxine 5-phosphate gave a maximum velocity that was 5.6-fold greater than with pyridoxamine 5-phosphate and showed strong substrate inhibition at above 6 microM. Among the tryptophan metabolites, picolinate, xanthurenate, quinolinate, tryptamine and 5-hydroxytryptamine inhibited pyridoxal kinase. However, pyridoxamine 5-phosphate oxidase could not be inhibited by tryptophan metabolites, and on the contrary it was activated by 3-hydroxykynurenine and 3-hydroxyanthranilate. Regarding the metabolism of vitamin B-6 in the liver, the effects of tryptophan metabolites that were accumulated in vitamin B-6-deficient rats after tryptophan injection were discussed.