Isolation of a β-carboline alkaloid from the leaves ofAllium tuberosum

(?)-(3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid and L-tyrosine were isolated from the leaves ofAllium tuberosum and characterized by spectral analysis. The isolation of the former compound from the natural sources is being reported for the first time.     

Comparative effects of β-carbolines on platelet aggregation and lipid membranes

The effects of 14 β-carbolines on human platelet aggregability were comparatively studied, and the effects on lipid membranes were determined. Several β-carbolines inhibited platelet aggregation induced by collagen, epinephrine, adenosine 5'-diphosphate, platelet-activating factor and thrombin. This activity was structure-dependent. Of all the compounds examined, 1-methyl-1,2,3,4-tetrahydro-β-carboline was the most potent. Treatment with 15-177 μM 1-methyl-1,2,3,4-tetrahydro-β-carboline inhibited the aggregation responses to different stimulants by up to 50%. Its potency was comparable to or greater than that of the antiplatelet reference, aspirin. The next most effective compound was 1-methyl-3,4-dihydro-β-carboline. The structure-antiplatelet activity relationship indicated that this activity is reduced by oxidation to 1-methyl-β-carboline, by demethylation to 1,2,3,4-tetrahydro-β-carboline and by 6-hydroxylation, 7-hydroxylation and 3-carboxylation. Active 1-methyl-1,2,3,4-tetrahydro-β-carboline fluidized biomimetic membranes at 25-250 μM which corresponded to the antiaggregatory concentrations, although relatively inactive 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline showed no significant effects on the membranes. β-Carbolines are considered to be effective antiplatelet agents that inhibit human platelet aggregation by interacting with lipid membranes to modify fluidity.     

1H- und 13C-NMR-spektroskopische Zuordnung der cis- und trans-Isomere einiger 1-Aryl-1,2,3,4-tetrahydro-β-carbolin-3-carbonsäuren bzw. deren Methylester

¹H- and ¹³C-NMR Spectroscopic Assigment to the cis and trans Isomers of Some 1-Aryl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic Acids and their Methyl Esters The cis and trans isomers of the tetrahydro-β-carbolines 3 and 4 were assigned on the basis of the shifts of the NMR signals of the proton at C-1 and of the carbon atoms C-1 and C-3.     

Untersuchungen zur Biosynthese des Harmins

The biosynthesis of harmine in Peganum harmala has been studied using labelled compounds. With the exception of the carboxyl group the carbon atoms and the nitrogen atom of the alanine side chain are incorporated into harmine from tryptophan. Tryptamine-(β-¹⁴C-¹⁵N) is practically an equally good precursor as tryptophan-(β-¹⁴C-¹⁵N). In order to clarify the origin of the C₂-unit of the β-carbolines (C-1 and C-10 of harmine) acetate-1-¹⁴C, acetate-2-¹⁴C, pyruvate-2-¹⁴C and pyruvate-3-¹⁴C were administered to young plants of P. harmala. A specific incorporation was observed after feeding pyruvate-2-¹⁴C into C-1 of harmine and pyruvate-3-¹⁴C into C-10 of harmine. An unspecific labelling pattern was observed after feeding of acetate-¹⁴C. 1-Methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid is no intermediate in the harmine-biosynthesis.     

Thrombocytenaggregationshemmung durch 1,2,3,4-Tetrahydro-β-carboline: Ein Hinweis auf serotoninantagonistische Eigenschaften dieser Substanzklasse

Inhibition of Platelet Aggregation by 1,2,3,4-Tetrahydro-β-carbolines: Evidence for 5-Hydroxytryptamine Antagonistic Activities Six 1,2,3,4-tetrahydro-β-carbolines were tested for platelet aggregation inhibiting activities. The aggregation induced by 5-hydroxytryptamine (5-HT) in human platelets was strongly inhibited. The most active compound 6-trifluoromethyl-1,2,3,4-tetrahydro-β-carboline was equipotent to chloropromazine (IC₅₀ = 4 · 10^?7 M). It is suggested that the inhibition is due to 5-HT antagonistic actions. Three compounds showed in vitro direct anticoagulant effects (Quick-time).     

Endogenous formation of 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in man as the possible causative substance of eosinophilia-myalgia syndrome associated with ingestion ofl-tryptophan

1-Methyl-1,2,3,4-tetrahydro--carboline-3-carboxylic acid (MTCA) is now thought to be a possible causative substance of eosinophilia-myalgia syndrome associated with ingestion ofl-tryptophan. In the present study a factor affecting endogenous formation of MTCA in 32 healthy men is studied. Urinary excretions of MTCA and 1,2,3,4-tetrahydro--carboline-3-carboxylic acid (TCCA) were measured by high-performance liquid chromatography (HPLC) with fluorometric detection after administration of a high or low protein diet as well as peroral tryptophan (0.5 g) or ethanol (0.4 g/kg). Blood ethanol and acetaldehyde levels were determined by gas chromatography after ethanol consumption. Both, the high protein diet and tryptophan resulted in a significant rise of urinary TCCA. In contrast, ethanol intake caused increased excretion of MTCA, though a relationship between blood acetaldehyde level and urinary excretion of MTCA was not shown. We showed for the first time that an elevation of urinary excretion of MTCA following ethanol consumption in man without ingestion ofl-tryptophan tablets implicated eosinophilia-myalgia syndrome.     

Peripheral Metabolism of β-Carboline-Carboxylic Acid Esters

Abstract: Esters of β-carboline-3-carboxylic acid have recently been identified as potent inhibitors of brain benzodiazepine receptors in vitro. Ethyl β-carboline-3-carboxylate (β-CCE), however, is a rather weak inhibitor in vivo of benzodiazepine receptors in mice. The ED50-value was 91 mg/kg intraperitoneally 35 min. after administration (ED50 is that dose which inhibits by 50% the specific binding of ³H-flunitrazepam intravenously). ED50 for β-CCE was 2–20 fold lower in mice pretreated with organophosphorus esterase inhibitors, concomitantly with the observation of strong inhibition of liver and kidney hydrolyzing activity, using ³H-propyl β-carboline-3-carboxylate as substrate. The rat brain contains only approximately 0.1% of the hydrolyzing activity as compared to the liver. It is concluded that some esters of β-carboline-3-carboxylate exhibit only weak effects on benzodiazepine receptors in living animals due to hydrolysis outside the brain.     

Identification and measurement of 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline by gas chromatography-mass spectrometry

A glass capillary gas chromatographic-mass spectrometric method for the analysis of 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline in urine, plasma and blood platelets was developed. The method involves the use of a deuterated analogue as internal standard, addition of semicarbazide, extraction with methylene chloride and formation of pentafluoropropionyl derivatives. The 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline was found to occur in the urine of controls and alcoholics as both the free and conjugated compound. In the controls the mean level of free and conjugated 6OMTHBC was 75 ± 20 nmole/1. When intoxicated, the alcoholics had a statistically higher excretion rate of the conjugate(s) than the controls. The compound was not detectable in blood platelets or plasma.     

A new norlignan lignanoside from Selaginella moellendorffii Hieron

This study reports an investigation into the chemical constituents of the whole plant of Selaginella moellendorffii Hieron. Ten compounds, isolated and purified by column chromatography, were identified on the basis of spectral analysis and their physicochemical properties to be: (8R)-3,5-dimethoxy-4-hydroxyphenylpropylalcohol-8-(1-acetyl-3-methoxy-4-hydroxyphenyl)-9-O-β-d-glucopyranoside (moellenoside B) (1), amentoflavone (2), hinokiflavone (3), apigenin-7-O-β-neohesperidoside (4), apigenin-8-C-β-d-glucopyranoside (5), adenosine (6), uridine (7), 2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid (8), vanillic acid (9), and lariciresinol (10). Compound 1 is a new norlignan lignanoside and compounds 4–10 were isolated from this plant for the first time.     

SK&F 83959 and non-cyclase-coupled dopamine D1-like receptors in jaw movements via dopamine D1-like/D2-like receptor synergism

This study compared the effects of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro- 1 H-3-benzazepine), which inhibits the stimulation of adenylyl cyclase, and A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman), a full efficacy agonist, in regulating jaw movements in the rat by synergism with dopamine D2-like receptor agonism. When SK&F 83959 and A 68930 were given in combination with quinpirole, there was a synergistic induction of jaw movements. Responsivity to SK&F 83959 + quinpirole was antagonised by the dopamine D1-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-ben zaz epine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline); synergism was antagonised also by the dopamine D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-++ +methyl-aminobenzamide). Responsivity to A 68930 + quinpirole was enhanced by low doses of SCH 23390, BW 737C and YM 09151-2, and antagonised by higher doses of SCH 23390 and YM 09151-2. These results implicate a novel, dopamine D1-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and suggest that its functional role extends to the regulation of jaw movements by synergistic interactions with dopamine D2-like receptors.     

Topographical assessment and pharmacological characterization of orofacial movements in mice: dopamine D(1)-like vs. D(2)-like receptor regulation

A novel procedure for the assessment of orofacial movement topographies in mice was used to study, for the first time, the individual and interactive involvement of dopamine D(1)-like vs. D(2)-like receptors in their regulation. The dopamine D(1)-like receptor agonists A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman) and SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine) each induced vertical jaw movements with tongue protrusions and incisor chattering. The dopamine D(1)-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) antagonised these responses, while the dopamine D(2)-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide) attenuated those to SK&F 83959 and released horizontal jaw movements. These findings suggest some role for a dopamine D(1)-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and for dopamine D(1)-like:D(2)-like receptor interactions, in the regulation of individual orofacial movement topographies in the mouse. This methodology will allow the use of knockout mice to clarify the roles of individual dopamine receptor subtypes in their regulation.     

Effects of garlic and black grape extracts on the activity of adenosine deaminase from cancerous and noncancerous human urinary bladder tissues

Aim Possible effects of garlic (Allium sativum) and black grape (Fructus vitis minuta) with known antioxidant potential on adenosine deaminase (ADA) activities were investigated in cancerous and noncancerous human bladder tissues. Methods The effects of garlic and black grape extracts on adenosine deaminase (ADA) activities were measured in 20 pairs of cancer and adjacent normal human bladder tissues with and without pre-incubation with garlic and black grape extracts at different concentrations. Results No significant difference was observed between ADA activities in cancerous and non cancerous bladder tissues without plant extract (5.85 ± 3.78 versus 7.63 ± 2.88, respectively). At the 1/3 and 1/1 plant extract/bladder tissue homogenate ratios, the garlic extract completely abolished the ADA activity in both cancerous and noncancerous tissues. At the 1/3 plant extract/bladder tissue homogenate ratio, the black grape extract decreased the activity significantly as compared to without extract (2.01 ± 1.30 versus 5.85 ± 3.78; p < 0.05 for cancerous tissue and 2.10 ± 1.66 versus 7.63 ± 2.88; p < 0.05 for noncancerous tissue) and, at the 1/1 plant extract/bladder tissue homogenate ratio, completely abolished the activity. Conclusion Our results show that garlic and black grape have potential to inhibit ADA activity in both cancerous and adjacent normal human bladder tissues.We suggest that this might be rational basis for the uses of garlic and black grape in the complementary therapy of urinary bladder cancer.     

Hyperactivity induced by tetrahydroisoquinoline derivatives injected into the nucleus accumbens.

Several derivatives of tetrahydroisoquinoline were injected bilaterally into the nucleus accumbens of rat 2 h after a nialamide pretreatment and activity recorded in cages fitted with photocells. 1,2,3,4-Tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-6,7-dihydroxy-1-(3,4-dihydroxybenzyl)-isoquinoline (tetrahydropapaveroline) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused virtually no change in locomotor activity and 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused only modest hyperactivity responses. However, 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both shown to markedly increase activity in a dose-dependent manner. Of these two compounds, the 3-methyl-6,7-methylenedioxyderivatives was most active and equalled the effectiveness of dopamine. The responses to dopamine and to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both threshold at 3.125 mug and maximum at 50 mug. Both effects developed within 1-2 h and persisted for at least 6 h. The hyperactivity induced by dopamine was antagonised in a dose-dependent manner by haloperidol: propranolol and aceperone were without effect. Similar results were obtained for these blocking agents against the responses to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline but aceperone and propranolol, in addition to haloperidol, were shown to inhibit the hyperactivity induced by 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.     

Alcohol drinking in the rat: Increases following intracerebroventricular treatment with tetrahydro-β-carbolines

Voluntary alcohol intake has been reported to increase in rats after the repeated intracerebroventricular (ICV) administration of 1,2,3,4-tetrahydro-β-carboline (THBC) and some tetrahydroisoquinolines, although negative results have also been reported. THBC is a normal constituent in human plasma and platelets; 1-methyl-1,2,3,4-tetrahydro-β-carboline (1-Me-THBC), however, occurs in the blood after a person drinks alcohol. We have evaluated the effects of two doses of THBC and 1-Me-THBC on voluntary alcohol consumption in rats. ICV infusions were given with Alzet® minipumps for 14 days rather than giving repeated ICV injections. Stability of the drugs in the pump was verified using mass spectrometry. On each day the rats chose between water, alcohol (increasing concentrations from 3 to 30%) and an empty bottle. Alcohol intake increased by about 100%(p<0.05) during the last six days when 47 nmoles/hr of either THBC or 1-Me-THBC was infused. At the end of the experiment elevated blood concentrations of alcohol (0.02–0.78%) were found in rats belonging to the THBC or 1-Me-THBC groups and drinking 30% alcohol. The infusion of 0.47 nmoles/hr of either drug did not increase alcohol intake as compared to control.     

Disposition of 3H-enisoprost,a gastric antisecretory prostaglandin,in healthy humans

1. After oral administration of ³H-enisoprost (450 μg) to five healthy men, as a solution in capsules, peak ³H levels of 5624 ± 566 pg equiv./ml (mean ± S.E.M.) were reached within one hour. No unchanged drug was detected in plasma.

2. Enisoprost was rapidly de-esterified to SC-36067 [(±)11α, 16ζ-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651±200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of β-oxidation, β-oxidation and 9-keto-reduction.

3. After nine days 59.0±2.98% and 17.4±1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days.

4. Five urinary metabolites were identified by GC-MS. These were (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-3α-hydroxy-5-oxo-1α-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (±)3-[3α,5-dihydroxy-2β-(4-hydroxy-4-methyl-1E-octenyl)-1α-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (±)3-[2β-(8-carboxy-4-hydroxy-4-methyl-1E-octenyl)-3α-hydroxy-5-oxo-1α-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (±)3-[2β-(8-carboxy-4-hydroxy-4-methyl-1E-octenyl)-3α,5-dihydroxy-1α-cylopentanyl]propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its γ lactone (2.6% dose).

5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1α-cyclopent-3-enyl]propaloic acid and (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1-enyl]propanoic acid.

6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11α-hydroxy group in SC-36067 or its metabolites also occurred.     

Dopamine analogous piperidines and piperazines (author's transl)]

Dopamine Analogous Piperidines and Piperazines Structure-activity relationships of 22 piperidines and piperazines structurally related to dopamine were investigated. The most active compounds show a profile (including dose range and spectrum) similar to that of haloperidol. The structural relationship of these compounds to dopamine analogous 1,2,3,4-tetrahydro-β-carbolines¹ is reflected in their action pattern.     

Untersuchungen zur „Carbolin-Blau-Reaktion”︁

The Carboline Blue Reaction In the course of the carboline blue reaction 1,2,3,4-tetrahydro-β-carbolines with an unsubstituted A ring (yohimbine type compounds) are oxidised by Fe³⁺ ions in concentrated sulfuric acid via the intermediate 6,9′-bi-1,2,3,4-tetrahydro-β-carbolines 2 to yield the cyanine chromophor 3 . 7-Methoxy-1,2,3,4-tetrahydro-β-carbolines (reserpine type compounds) are oxidised by the same reagents via the intermediate 7,7′-dimethoxy-8,8′-bi-1,2,3,4-tetrahydro-β-carbolines 5 to yield the cyanine type chromophor 6 . The specificities of these colour reactions are discussed.     

Topographical resolution of jaw movements mediated by cyclase- vs. non-cyclase-coupled dopamine D(1)-like receptors: studies with SK&F 83822

This study examined the effects on orofacial movement topography of SK&F 83822 ([R/S]-6-chloro-7,8-dihydroxy-3-allyl-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), which stimulates dopamine D(1)-like receptors coupled to stimulation of adenylyl cyclase (AC) but not phosphoinositide (PI) hydrolysis, in comparison with SK&F 83959 ([R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), which stimulates PI hydrolysis but not AC. SK&F 83822 alone induced chattering, while SK&F 83959 alone exerted little effect. SK&F 83822 and SK&F 83959 each in combination with the dopamine D(2)-like agonist quinpirole resulted in synergistic induction of non-chattering movements with tongue protrusions. These effects were blocked by the dopamine D(1)-like receptor antagonist SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). However, the dopamine D(2)-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide) exerted a biphasic effect on synergism with SK&F 83822: chattering was initially released but antagonised thereafter. Only antagonism was seen for synergism with SK&F 83959. While both AC- and PI-coupled dopamine D(1)-like receptors participate in synergistic dopamine D(1)-like:D(2)-like receptor interactions, topographically specific synergistic and oppositional dopamine D(1)-like:D(2)-like interactions evident with SK&F 83822 reflect the involvement primarily of D(1)-like receptors coupled to AC rather than PI.     

Excretion and distribution of nitrite-treated or untreated 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid in rats

The excretion and distribution of 14C were studied in rats given by oral intubation 14C-labelled (-)-(1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and its stereoisomer, (-)-(1R,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCAs), compounds that are known to become mutagenic on reaction with nitrite. For comparison, another group of rats was given by oral intubation products of the in vitro treatment of [14C]MTCAs with nitrite. When rats were given the untreated [14C]MTCAs, most of the 14C was excreted in the faeces within 24 hr and was noted only in the intestine on autoradiograms of rats killed 30 min and 6 hr after dosing. In contrast, when rats were given the nitrite-treated [14C]MTCAs, 14C was mainly excreted in the urine within 24 hr and was noted not only in the intestine but also in the liver and kidney on autoradiogram. These results suggest that the majority of MTCAs pass rapidly through the gastro-intestinal tract, while the bulk of the reaction products of MTCAs with nitrite are absorbed from the gastro-intestinal tract and excreted in the urine.     

Synthesis and properties of amides of 1-benzyl-3-methyl- and 1-butyl-3-phenyl-7-methyl-4-oxo-2-thioxo (2,4-dioxo)-1,2,3,4-tetrahydropyrido-[2,3-d]pyrimidine-6-carboxy lic acids

Amides of 1-benzyl-3,7-dimethyl-4-oxo-2-thioxo-1,2,3,4- tetrahydropyrido[2,3]pyrimidine-6-carboxylic acid were obtained by the condensation of ammonia, primary and secondary cyclic amines with the corresponding acid chloride. As by - products amides of 1-benzyl-3,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyr imidine-6- carboxylic acid were isolated as a result of desulfuration. The same reaction performed with chloride of 1-butyl-7-methyl-3-phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyri do[2,3- d]pyrimidine-6-carboxylic acid gave mainly the corresponding 2,4-dioxo-amides.