Β-carboline Derivatives Research Articles

A search for quantum mechanical methods suitable for the conformational analysis of models related to some inverse agonists of the benzodiazepine receptor

The target of this work consists in a search, among several methods of quantum mechanical calculations, for the most suitable one (both with regard to accuracy and speed) for doing conformational analysis on models related to molecules belonging to a group of indol-3-yl glyoxylyl derivatives, many of which behave as ligands of the benzodiazepine receptor (BzR). Among the wide variety of ligands of the BzR, β-carboline derivatives are included, many of which show a pharmacological profile similar to the one exhibited by compounds of interest to us. A structure analogy between our compounds and β-carboline derivatives could be hypothesized, depending upon the preferred arrangement of the investigated molecules with respect to the dihedral angles of the indol glyoxylyl moiety. Therefore a potential energy surface scan has been carried out on selected models either by the quantum mechanical semiempirical methods MNDO, AM1, PM3 (by using the programs included in themopac package) or by a quantum mechanical SCFab initio method (by using thegaussian-80 program), both in order to find support for the choice of the more suitable semiempirical method, and in order to verify a structural analogy between our compounds and the β-carboline ring. The results showed that AM1 and PM3, unlike MNDO, seem to be suitable semiempirical methods for doing potential energy surface scans on this kind of molecule. The preferred arrangement showed by the models with respect to the indol glyoxylyl moiety appeared to support the hypothesis about the structure analogy between the investigated ligands and β-carboline derivatives.

Biosynthetic studies of eudistomin H in the tunicate Eudistoma olivaceum

Eudistomin H ( 1) is an antibiotic alkaloid isolated from the tunicate Eudistoma olivaceum. In our continuing investigation of the biosynthetic origin of β-carboline derivatives in this marine invertebrate, we have evaluated 5-bromotryptamine and 5-bromotryptophan as intermediates. Both of these amino acid derivatives served efficiently as precursors to eudistomin H.

Relationship between occurrence of tremor/convulsion and level of β-carbolines in the brain after administration of β-carbolines into mice

Fifteen β-carboline derivatives, including those found in the South American hallucinogenic plant Banisteriopsis caapi, were injected IP and IVC into mice. Subsequent behavioral changes were observed and the levels of the compounds in brain tissue were determined. It was found that following IP administration, tremors and/or convulsions were induced by β-carbolines having aliphatic alkyl groups, but not by those with carbonyl and oxo groups substituted at carbon-1 of the C ring. These effects were potentiated by the presence of a methoxy group at carbon-7 of the A ring, and their durations of actions were prolonged by 3,4-dihydro derivatives. When induced, tremors/convulsions correlated with levels of β-carbolines in the brain. The smaller ED 50 values of β-carbolines that cause tremors/convulsions showed lower levels of β-carbolines in brain tissue.

Spectroscopic study of molecular associations between FMN and β-carbolines

The spectrophotometric and thermodynamic properties of molecular complexes of flavin mononucleotide (FMN) (riboflavin 5′-phosphate) with some β-carboline derivatives have been investigated in aqueous solution. The molecular associations have been examined by means of electronic absorption spectra, since in each a new charge-transfer band has been located, and also the variation of the fluorescence emission of FMN on the solutions has been observed. The formation constants for the molecular complexes were determined from absorption data using the Foster—Hammick—Wardley method. The quenching phenomenon observed in FMN fluorescence is related to the concentration of the β-carboline derivatives, allowing the calculation of the quenching constants for FMN-β-carboline complexes. Thermodynamic parameters have been determined from the values of association constants for the molecular complexes at various temperatures. The influence of substituents in the β-carboline molecule on the stability of the complexes formed was also investigated.

Degeneration of purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline

The indole alkaloids ibogaine and harmaline are β-carboline derivatives that cause both hallucinations and tremor. Reports that ibogaine may have potent anti-addictive properties have led to initiatives that it be tested for the treatment of opiate and cocaine addiction. In this study, ibogaine-treated rats were analysed for evidence of neurotoxic effects because human clinical trials of ibogaine have been proposed. We recently found that ibogaine induces a marked glial reaction in the cerebellum with activated astrocytes and microglia aligned in parasagittal stripes within the vermis. 28 Based on those findings, the present study was conducted to investigate whether ibogaine may cause neuronal injury or degeneration. The results demonstrate that, after treatment with ibogaine or harmaline, a subset of Purkinje cells in the vermis degenerates. We observed a loss of the neuronal proteins microtubule-associated protein 2 and calbindin co-extensive with loss of Nissl-stained Purkinje cell bodies. Argyrophilic staining of Purkinje cell bodies, dendrites and axons was obtained with the Gallyas reduced silver method for degenerating neurons. Degenerating neurons were confined to narrow parasagittal stripes within the vermis. We conclude that both ibogaine and harmaline have selective neurotoxic effects which lead to degeneration of Purkinje cells in the cerebellar vermis. The longitudinal stripes of neuronal damage may be related to the parasagittal organization of the olivocerebellar climbing fiber projection. Since these drugs produce sustained activation of inferior olivary neurons, we hypothesize that release of an excitatory amino add from climbing fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje cells.

Spectroscopic study of molecular associations between riboflavin and some (dihydro) β-carboline derivatives

Abstract The spectrophotometric and thermodynamic properties of molecular complexes of riboflavin (RFN) with some dihydro β-carboline derivatives have been investigated by using electronic absorption and fluorescence spectroscopic methods in aqueous solution. The molecular associations have been examined by means of eletronic absorption spectra, since in each, a new charge transfer-like band has been located, and also by observing the variation of the fluorescence emission of RFN on the solutions. The formation constants for the molecular complexes were determined from absorption data, using the Forster—Hammick—Wardley method. The quenching phenomenon observed in RFN fluorescence is related to the concentration of the dihydro β-carboline derivatives, allowing the calculation of the quenching constants for RFN—β-carboline complexes. Thermodynamic parameters have been determined from the values of association constants for the molecular complexes at various temperatures. The influence of substituents in the dihydro β-carboline molecule on the stability of the complexes formed was also investigated.

Acid–base and spectral properties of β-carbolines. Part 2. Dehydro and fully aromatic β-carbolines

The absorption and fluorescence spectra of a set of dehydro and fully aromatic β-carboline (9H-pyrido[3,4-b]indole) derivatives have been investigated in aqueous solutions of varying acidity. Within the pH-range, cationic (nitrogen protonation) and neutral species are evidenced from both absorption and fluorescence spectra. Additional zwitterionic species can also be detected from the fluorescence spectra. In highly basic media, outside the pH-range, anionic species (pyrrolic nitrogen deprotonation) are formed. Ground state ionization constants for the different acid–base equilibria involving these species have been determined spectrophotometrically at 25 °C. Lowest excited singlet state pKas have been estimated from the Forster–Weller cycle. The influence of structural variations on the spectra and on the acid–base properties of these compounds is discussed.

天然物の全合成 アルカロイドからテルペンまで

This review describes the studies on the total syntheses of the natural products, particularly alkaloids and terpenes, which involves the determination of absolute configurations of emetine, yohimbin and reserpine. It has been attempted in principle that the synthesis should be developed by utilization of the new reactions originated in our own laboratory. The successful syntheses are demonstrated by “one-step synthesis of β-carboline derivatives”, “development of a new synthetic method for 3, 3-disubstituted oxindole derivatives, which method was extended to the synthesis of various indole alkaloids through a common intermediate”, “the total synthesis of strychnos, aspidosperma and schizozygane alkaloids by photo-isomerization of 1-acylindole to 3-acylindolenine”, “the crisscross annulation for syntheses of heterocycles and the natural products” and “bis trimethylsilyl enol ether has been utilized as a 'masked acyl anion'for the synthesis of terpenses and the biologically active cyclic lactones”.

Some β-carboline derivatives as fluorescence standards

We present in this work a study on the standard properties of five β-carboline derivatives: nor-harmane or β-carboline, harmane, harmine, 2-methyl harmine and harmaline in H 2SO 4 aqueous solutions. The cationic species absorb and emit in these media, therefore, we have measured the fluorescence quantum yield and lifetime values of cationic species. Fluorescence spectra of these five cationic species cover a region between 400–560 nm. These five spectra show a strong overlapping.

Short synthesis of tryptophane and β-carboline derivatives by reaction of indoles withN-(diphenylmethylene)-α,β-didehydroamino acid esters

The ethylaluminum dichloride catalyzed Michael-type addition of indoles 1a-h to the N-(diphenylmethylene)-α,β-didehydroamino acid esters 2a-c allows a new synthesis of β-methyltryptophanes 41,m and a new route for 1,1-diphenyl-3-carbalkoxy-1,2,3,4-tetrahydro-β-carbolines 5a-m.

New uses of Westphal condensation: Synthesis of flavocorylene and related indolo[2,3-a]quinolizinium salts.

Using the Westphal condensation, flavocorylene and related Indolo[2,3-a]-quinolizinium salts have been prepared in two steps, starting from commercially available β-carboline derivatives.

Effect of β-carboline derivatives on the binding of l-tryptophan and diazepam to bovine and human albumin

The effects of 12 β-carboline derivatives on the binding of l-tryptophan and diazepam to bovine and human albumin have been investigated to seek similarities between the indole binding site on albumin and the benzodiazepine receptor in the brain. The binding of l-tryptophan and diazepam was measured at 37° and pH 7.4 by equilibrium dialysis. Norharmane was the most potent inhibitor of the binding of l-tryptophan and diazepam to both bovine and human albumin. The kinetics of the inhibitory effects of several of the β-carbolines were studied. Norharmane decreased the value ( n) for the number of binding sites for the binding of l-tryptophan to both bovine and human albumin. Norharmane and harmane decreased the apparent association ( K a) but increased n for the interaction of diazepam with bovine albumin. Norharmane also had a similar effect on the binding of diazepam to human albumin. The similarities between the inhibitory effects of the β-carbolines on the binding of l-tryptophan and diazepam to albumin and the affinity of the β-carbolines for the central benzodiazepine receptor point to some common structural requirements for binding to the receptor and to albumin.

Abnormal Behaviors Induced by β-Carboline Derivatives in Mice

Abnormal Behaviors Induced by β-Carboline Derivatives in Mice

The regulation of high-affinity choline uptake in vitro in rat cortical and hippocampal synaptosomes by β-carbolines administered in vivo

The effects of several β-carboline derivatives on sodium-dependent high-affinity choline uptake (HACU) were investigated in rat hippocampus and cerebral cortex. HACU was measured in synaptosomal preparations from these areas after in vivo administration of the drugs. The convulsant, picrotoxin (6 mg/kg), stimulated HACU in both hippocampal and cortical synaptosomes. The convulsant inverse agonist benzodiazepine, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) (5 mg/kg) stimulated hippocampal but not cortical HACU. However, other inverse agonists, methyl-β-carboline-3-carboxylate (β-CCM) (20 mg/kg) and ethyl-β-carboline-3-carboxylate (β-CCE) (20 mg/kg), stimulated HACU in the cortex but not in the hippocampus. The partial inverse agonist, N-methyl- β-carboline-3-carboxylate (FG-7142) (20 mg/kg), inhibited cortical HACU and had no effect on hippocampal HACU. The antagonist β-carboline, 3-hydroxymethyl-β-carboline (3-HMC) (20 mg/kg), had no effect on either cortical or hippocampal HACU. None of these drugs displayed any effect on HACU when they were incubated directly in vitro with synaptosomal preparations at concentrations up to 100 μM, suggesting their activity is not directly on the cholinergic nerve terminal. The results suggest that β-carbolines regulate hippocampal and cortical cholinergic activity as do other GABAergic drugs. However, unlike diazepam, which depresses cholinergic activity in both the hippocampus and the cortex the β-carbolines differentiate between the hippocampus and cortex in their action.

Thymopentin antagonizes stress-induced changes of GABA/benzodiazepine receptor complex

Intraperitoneal administration of thymopentin, a thymopoetin II-derived pentapeptide, had no stable and evident effect in the two anxiety models (elevated plus-maze and licking-conflict test) studied. However, in the elevated plus-maze test thymopentin antagonized the behavioral effects of DMCM, a β-carboline derivative with anxiogenic properties. Further, it was demonstrated that the licking-conflict test procedure itself produced a significant elevation of plasma corticosterone levels, increased the number of [ 3H]flunitrazepam and decreased the number of [ 3H]muscimol binding sites in rat hippocampus. The forced-swimming stress similarly to the licking-conflict test also caused an increase in hippocampal [ 3H]flunitrazepam binding sites. Although ineffective behaviorally in the tests for anxiety, thymopentin pretreatment effectively reversed the changes in corticosterone levels caused by the licking-conflict test. Moreover, it normalized the changed number of benzodiazepine and GABA receptors after stressful stimuli. It is well known that not all anxiolytic drugs (i.e. buspirone) are equally active in behavioral tests for anxiety. According to our data we propose that thymopentin has stress-protective activity. As in vivo and in vitro thymopentin did not change [ 3H]flunitrazepam and [ 3H]muscimol binding, the direct effect of this peptide on the GABA-benzodiazepine-Cl − ionophore receptor complex is unlikely. The action of this peptide on GABA release and/or metabolism can be suggested.

Detection of Direct-Acting Mutagens and Compounds Mutagenic after Nitrite Treatment from Broiled Mutton

We previously reported the mutagenic activities of dailyfoodstuffs classified into 13 groups (I-XIII) by a market basket method. The mutagenic activities were generally increased by nitrite treatment under acidic conditions. In this study, methanol extracts of seven foodstuffs in group XI (meats, egg), which showed weak direct mutagenic activity and high mutagenic activity after nitrite treatment, were subjected to the Ames test using S. typhimurium TA 100 strain without metabolic activation. The mutagenic activity of group XI was mainly due to meats such as chicken, pork, beef and mutton. In particular, the mutagenic activity of mutton treated with nitrite increased to 3.9 times that of the untreated sample. It was demonstrated that the mutagens were produced during heating of the meat.From studies on the detection of mutagens in broiled mutton by using gas chromatography, high performance liquid chromatography, and gas chromatography-mass spectrometry, three α-dicarbonyl compounds (glyoxal, methylglyoxal and diacetyl) were identified as directacting mutagens. Furthermore, four tryptophan-related compounds (5-hydroxyindole, tryptamine, L-tryptophan and 5-hydroxytryptamine) and two β-carboline derivatives ((1R, 3S)-and (1S, 3S) -1, 2, 3, 4-tetrahydro-1-furyl-9H-pyrido [3, 4-b] indole-3-carboxylic acid) were identified as premutagens which show an increase of mutagenic activity after nitrite treatment.

Generation of a .BETA.-carboline derivative, the yellowish precursor of processed radish roots, from 4-methylthio-3-butenyl isothiocyanate and L-tryptophan.

(1990). Generation of a β-Carboline Derivative, the Yellowish Precursor of Processed Radish Roots, from 4-Methylthio-3-butenyl Isothiocyanate and l-Tryptophan. Agricultural and Biological Chemistry: Vol. 54, No. 7, pp. 1849-1851.

Inhibition of sleep and benzodiazepine receptor binding by a β-carboline derivative

The effects of systemic injections of β-carboline-3-carboxylate- t-butyl ester (β-CCtB) were investigated with regard to normally occurring sleep and several measures of benzodiazepine receptor occupancy in rats. A dose of 30mg/kg of β-CCtB was found to have a long time-course of action as measured by an in vivo assay for benzodiazepine binding, with an 84% depletion of [ 3H]diazepam binding at one hour after the intraperitoneal injection. This dose of β-CCtB was shown to delay sleep onset, decrease non-REM and total sleep in the first two hours after the injection, and to delay the appearance of REM sleep after the sleep onset. The dose- and time-dependence of the effects on sleep approximated the dose- and time-dependence of inhibitory effects of an IP injection of β-CCtB on in vitro measures of benzodiazepine receptor affinity and number.

ChemInform Abstract: Sulfonation Reactions of β‐Carbolines.

AbstractKinetics and the different mechanisms of the homogeneous sulfonations of β‐carboline derivatives (I)‐(III) are studied.

Determination of β-Carboline Derivatives in Biological Samples by High-Performance Liquid Chromatography with Fluorescence Detection

An assay procedure for measuring plasma, urine, and feces levels of seven β-carbolines and possible metabolites is described. The drugs are extracted with diethylether or, alternatively, with a commercially available automated extraction device after adding an appropriate internal standard. Separation from matrix constituents is performed by reversed-phase high-performance liquid chromatography (HPLC) followed by fluorescence detection. The carboxylic acid metabolites of the β-carbolines have to be esterified before HPLC measurement. The detection limits are 0.2 ng/mL for β-carbolines and 2 ng/mL for their metabolites. Plasma levels and pharmacokinetic parameters of six different β-carbolines in healthy male volunteers following iv or po treatment are described. Total clearance ranged from 17 to 52 mL/min/kg and the terminal half-life ranged from 1 to 4h. The absolute bioavailability exhibited a range from <1 to 61%.