5-Methyltetrahydrofolic Acid as a Mediator in the Formation of Pyridoindoles

Mandel, L; Rosegay, Avery; Walker, Robert; Vandenheuvel, W.J.A.; Rokach, Joshua

doi:10.1126/science.186.4165.741

Cited by 85 publications

(10 citation statements)

References 12 publications

(9 reference statements)

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“…Acad. mation of f3-carbolines by animal tissue in vivo has not been demonstrated, but tetrahydro-f3-carboline derivatives may be synthesized in vitro from mixtures of tryptamines, methyl tetrahydrofolic acid, and brain or liver enzymes (42)(43)(44)(45). We are tempted, therefore, to speculate that f3-carboline-3-carboxylic acid can be formed in vivo by condensation of tryptophan and a Cl-unit (nonenzymatic Pictet-Spengler condensation?)…”

Section: Discussionmentioning

confidence: 99%

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Bræstrup¹,

Nielsen²,

Olsen³

1980

Proc. Natl. Acad. Sci. U.S.A.

472

169

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Benzodiazepines probably exert their anxiolytic, hypnotic, and anticonvulsant effects by interacting with brain-specific high-affinity benzodiazepine receptors. In searching for possible endogenous ligands for these receptors, we have purified a compound 107-fold from human urine by extractions, treatment with hot ethanol, and column chromatography. The compound was identified as ,-carboline-3-carboxylic acid ethyl ester (IIc) by mass spectrometry, NMR spectrometry, and synthesis; HIc was also isolated from brain tissues (20 ng/g) by similar procedures. Very small concentrations of TIc displaced [3H]diazepam completely from specific cerebral receptors, but not from liver andkidney binding sites; the concentration causing 50% inhibition of specific [3H]diazepam binding (IC50) was 4-7 nM compared to ca. 5 nM for the potent benzodiazepine lorazepam. Specific binding sites for quinuclidinyl benzilate, naloxone, spiroperidol, serotonin, muscimol, and WB 4101 were not affected by IIc. In contrast to benzodiazepines, I1c exhibits "mixed type" competitive inhibition of forebrain benzodiazepine receptors (negative cooperativity). We surmise that an endogenous ligand for benzodiazepine receptors may be a derivative of P-carboline-3-carboxylic acid.[3H]Diazepam and [3H]flunitrazepam bind specifically and with high affinity to brain membranes from all higher vertebrates, including man (1-5). Binding is brain specific (6), correlated to pharmacological potency (1, 7-10), located on neurons (11-17), distributed unevenly in the brain (6), and slightly sensitive to seizures and stressful conditions (18,19 5.5. Further impurities were removed by washing twice with 0.05 vol of borate buffer (100 mM, pH 9) and three times with 0.05 vol of aqueous NH3 (100 mM). All aqueous phases were washed twice in counter current fashion with ethyl acetate to decrease losses. The combined ethyl acetate phase was evaporated to dryness and the residue was dissolved in 300 ml of 0.18-0.25 M HCI and washed with 500 ml of diethyl ether, which removed large amounts of impurities. The active fraction was then extracted twice with 500 ml of diethyl ether at pH 5-5.5. After evaporation the brown-orange waxy residue was dissolved in 3 ml of 50% ethanol and chromatographed on a Sephadex LH-20 column [1.5 X 84 cm, elution volume (Ve) = 144 ml] in 50% ethanol. The active fraction (y-fraction) was eluted in a volume of [15][16][17][18][19][20][21][22][23][24][25]

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Section: Discussionmentioning

confidence: 99%

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Bræstrup¹,

Nielsen²,

Olsen³

1980

Proc. Natl. Acad. Sci. U.S.A.

472

169

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“…However, recent work suggests that formaldehyde is liberated during the incubation from both methyl donors leading to cyclized condensation products with indolealkylamines (Mandel et al, 1974;Leysen and Laduron, 1974b;Meller et al, 1974;Hsu and Mandell, 1975).…”

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confidence: 95%

Neurochemical investigations of the interaction of N,N-dimethyltryptamine with the dopaminergic system in rat brain

Maître

1977

Psychopharmacology

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Abstract. N,N-dimethyltryptamine (DMT) is a psychotomimetic indolealkylamine that has been suspected of being an endogenous causal factor in the aetiotogy of schizophrenia. Some aspects of its interaction with the dopaminergic system of the rat brain have been studied neurochemically, and comparisons have been made with the effects of d-amphetamine and apomorphine. In contrast to these two compounds, DMT has proved to be a potent, but short-acting MAO inhibitor with a rather selective effect on MAO A (serotonin-deaminating MAO).Like classical MAO inhibitors, DMT also greatly increases the accumulation of 3 H-dopamine plus 3 H-3-methoxytyramine newly formed from 3H-Dopa. Amphetamine and apomorphine have no comparable effect.Striatal levels of 3,4-dihydroxyphenylacetic acid are more efficiently lowered by DMT than those of homovanillic acid. The reverse has been observed with apomorphine, whereas amphetamine increases the concentrations of homovanillic acid and decreases those of 3,4-dihydroxyphenylacetic acid.Thus, in addition to its MAO inhibitory action, DMT probably also possesses dopamine-releasing effects. Both these properties could result in an indirect dopaminomimetic activity of DMT. It may be assumed, therefore, that the psychotomimetic activity of this compound is not only linked to its effects on cerebral serotonergic mechanisms, but to a combination of these with an indirect dopaminergic stimulant activity.

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“…An increased conversion of serine into glycine concomitantly results in an increased formation of CH2FH4 which can dissociate into FH4 and formaldehyde (Donaldson and Keresztesy, 1961). The latter substance may react spontaneousIy with monoamines forming isoquinolines and ß-carbolines (Leysen et al, 1974;Mandel et al, 1974;Lauwers et al, 1975;Meiler et a\., 1975). Normally, the CH2FH4 thus formed will be converted into CH3FH4 and the CH3 group will be subsequently transferred to homocysteineforming methionine.…”

Section: Entgleisung Des Cl-stoffwechsels Bel Episodischen Schlzoaffementioning

confidence: 97%

Derangement of One-carbon Metabolism in Episodic Schizoaffective Psychoses

Bruinvels¹,

Pepplinkhuizen²,

Fekkes³

1988

Pharmacopsychiatry

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The so-called cycloid or degeneration psychoses form a subgroup of the vaguely defined schizoaffective psychotic disorders, or according to the DSM III criteria: "Psychotic Disorders Not Elswhere Classified" (295.40; 298.80; 295.70; 298.90). Recovery from these acute psychoses is always complete, though episodic recurrence is commonly observed. The clinical syndrome is characterized by a kaleidoscopic, polymorphous clinical picture, e.g. sudden mood swings, motility disturbances, states of pananxiety and ecstasy with visionary experiences, perfunctory delusional ideas and visual hallucinations. At the onset of the psychoses many patients experienced psychedelic phenomena. It was postulated that these patients suffered from an abnormality in one-carbon metabolism resulting in the formation of beta-carbolines which were held responsible for evoking the psychotic symptoms. Since serine is the principle donor for one-carbon units, serine was administered to nonsymptomatic patients. Two to three hours after the administration patients became psychotic again. Analysis of blood samples from these patients showed a decreased fasting plasma concentration of serine and an increased fasting plasma level of taurine. In addition a decreased formation of serine from glycine was found. These findings are in agreement with the postulated derangement of one-carbon metabolism. Moreover, the beta-carboline norharman was present in blood obtained during acute psychotic episodes and was not present in blood of nonsymptomatic patients nor in blood of healthy controls. No abnormal activities of enzymes were found in skin fibroblasts from these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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5-Methyltetrahydrofolic Acid as a Mediator in the Formation of Pyridoindoles

Cited by 85 publications

References 12 publications

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Neurochemical investigations of the interaction of N,N-dimethyltryptamine with the dopaminergic system in rat brain

Derangement of One-carbon Metabolism in Episodic Schizoaffective Psychoses

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