Β-carboline Derivatives Research Articles

Sulfonation reactions of (β-carbolines

The homogeneous sulfonations of (β-carboline derivatives norharmane 2, harmane 3, harmine 4, harmol 5, -N,N′-dimethyl-harmane 6, and harmaline 7 have been studied in 80–90% w/w sulfuric acid solutions at 25 °C. Ultraviolet–visible and 13C nuclear magnetic resonance spectra and chemical analysis of the reaction mixtures show that for all the substrates studied only C-6 sulfonated products are obtained. The sulfonation reactions of the benzene unsubstituted substrates 2, 3, and 6 and the partially aromatic substrate 7 proceed by direct electrophilic attack of the H3SO4+ cation on the benzene ring of the (β-carboline skeleton. Sulfonation of 4 and 5 at the lower sulfuric acid concentrations is effected by the H3SO4+ entity. With increasing sulfuric acid concentration there is a gradual changeover of the sulfonating entity from H3SO4+ to H2S2O7. The different mechanisms of sulfonation are discussed. Keywords: β-carbolines, sulfonation, kinetics.

The β-carboline derivatives ZK 93426 and FG 7142 fail to precipitate abstinence signs in diazepam-dependent cats

The aim of the present study was to investigate the ability of different benzodiazepine recognition site antagonists (Ro 15-1788 and ZK 93426) and inverse agonists (Ro 15-4513, FG 7142 and CGS 8216) to induce abstinence signs in diazepam-dependent cats. Different groups of cats were challenged with each of the benzodiazepine recognition site ligands under investigation 24 hours after the last dose of chronic treatment with diazepam (7 mg/kg, IP at 8.00 a.m. and 8.00 p.m. for 21 consecutive days). The benzodiazepine derivatives Ro 15-4513 and Ro 15-1788 precipitated an abstinence syndrome within minutes after IP administration. The pyrazoloquinoline derivative CGS 8216 also induced withdrawal signs that were less severe and had a longer latency than those elicited by Ro 15-4513 and Ro 15-1788. Abstinence signs included tremors, increased muscle tone, irritability, fear, arched-back posture, pupillary dilation and vocalizations. On the other hand, the β-carboline derivatives ZK 93426 and FG 7142 failed to precipitate abstinence signs in induce withdrawal signs in diazepam-dependent cats depends on the chemical structure of the challenge drug (i.e., benzodiazepine or pyrazoloquinoline), since β-carboline antagonists like ZK 93426 and partial inverse agonists like FG 7142 lack this property.

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

The formation of molecular complexes between riboflavin (RFN) and some β-carboline derivatives (antidepressant drugs that have a pronounced inhibition of monoamine oxidase) has been studied by using electronic absorption and fluorescence spectroscopic methods in aqueous solution. The formation constants for the molecular complexes were determined from data of absorption, using the Foster–Hammick–Wardley method. The quenching phenomenon observed in RFN fluorescence is related to the concentration of the β-carboline derivatives, allowing the calculation of the quenching constants for RFN–β-carboline complexes. Thermodynamic parameters have been determined from the values of associations 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.

Electrophilic substitution in indoles. Part 17. The cyclisation of (dimethoxyphenylacetyl)tryptamines to spiropentacyclic indole derivatives

N-(3,4-Dimethoxyphenylacetyl)tryptamine (1a) cyclises with either phosphoryl chloride or phosphorus trichloride to afford the oxo spirocyclic indoline (10a) in 68% yield together with small amounts of β-carboline derivatives. Trifluoroacetic anhydride-catalysed cyclisation affords a virtually quantitative yield of the bis-N-trifluoroacetyl spirocyclic indoline (12). The latter undergoes hydrolysis with aqueous ammonia, followed by autoxidation, to afford (10a) in 95% yield.

A total synthesis of manzamine c

Manzamine C ( 1) was synthesized by the conjunction of 6-(Z)-azacycloundecene ( 9) and 1-substituted β-carboline derivatives ( 10 or 13)

Experimental and theoretical radiative lifetimes for some β-carboline derivatives

The photophysical properties (absorption and fluorescence spectra, quantum yields and fluorescence lifetimes) for neutral and cationic species of seven β-carboline derivatives were studied in ethanol solution. The ratio between experimental and theoretical radiative lifetimes was obtained. These values suggest that there is a configurational change between the ground state and the excited state. The Δp K values obtained from the Foster-Weller cycle corroborate this interpretation. The photophysical behaviour of these derivatives can also be explained in terms of the curves obtained by plotting energy vs. the β-carboline ring-proton distance.

Ro 15-4513, like anxiogenic β-carbolines, increases dopamine metabolism in the prefrontal cortex of the rat

The effects of Ro 15-4513, FG 7142 and β-CCM on the activity of the mesocortical dopaminergic system were examined by measuring the changes in the content of the principal dopamine (DA) metabolite, dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex of the rat. Ro 15-4513 increased the DOPAC content in the prefrontal cortex in a dose-dependent manner (5–40 mg/kg i.p.) but had no effect on DA concentrations. A similar increase in DOPAC content was induced by FG 7142 (40 mg/kg i.p.) and β-CCM (8 mg/kg s.c.), two β-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and β-CCM on DA metabolism in the prefrontal cortex are mediated via benzodiazepine recognition sites, since they were prevented by the administration of the benzodiazepine antagonists Ro 15-1788 and ZK 93426. These data indicate that Ro 15-4513 is an inverse agonist at benzodiazepine recognition sites.

Quantum yield and fluorescence lifetime measurements of neutral and cationic species for six β-carboline derivatives

A study of some emission parameters (quantum yield and fluorescence lifetime) for six alkaloid derivatives of β-carboline is presented. Depending on pH value, various species can exist in solution. In this work we have studied only two of them: cationic and neutral species (see fig. 1). The variation of quantum yield and fluorescence lifetime has been analysed for different substituted β-carboline rings and for some derivatives which do not present the aromatic character on the pyrimidinic nucleus.

ChemInform Abstract: Apparent Dipole Moments and Molar Volumes of β‐Carbolines and Carbazole in Dioxane Solution.

The apparent molecular polarization at infinite dilution, P2∞, molecular refraction, RD, dipole moment, µ2, and partial molar volume, V2°, of carbazole and some β-carboline derivatives have been determined from dielectric permittivity, specific volume, and refractive index measurements in 1,4-dioxane solutions at 25 °C. Evidence of hydrogen-bonding interaction with solvent has been found from i.r. spectroscopy and the apparent molar volumes. A relation has been found between literature pKa values of β-carboline derivatives studied in the ground state and their corresponding dipole moments in solution.

Possible occurrence of a β-carboline pathway in the oxidative catabolism of 5-hydroxytryptamine: Chemical approach and structure determination of a yellow substance and related β-carboline derivatives

The reaction of 5-hydroxytryptamine with severalfold excess silver oxide in a methanol medium at 65 to 70°C for several hours gave 6-hydroxy-3,4-dihydro-β-carboline ( I) as a main product. The yellow substance obtained in an aqueous system reported previously was identical to the latter compound with respect to NMR, field desorption (FD) mass spectroscopy, and other optical measurements. On the other hand, the same system in an ethanol medium gave 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline ( II) as a main product. It became clear from the following results that silver oxide reacted with methanol to produce formaldehyde, and thereafter oxidized the adduct of 5-hydroxytryptamine with formaldehyde to produce the yellow substance. The borohydride-reduced yellow substance was determined to be 6-hydroxy-1,2,3,4-tetrahydro-β-carboline. Anaerobic incubation of 5-hydroxytryptamine with formaldehyde in ethanol did not give rise to the yellow substance. Upon the addition of silver oxide or the addition of iron-EDTA under air to this system, the yellow substance was found. The C-1 unit of formaldehyde was utilized, being incorporated into the yellow substance. Although iron-EDTA catalyzed the oxidative reaction, EDTA itself could also act as a C-1 unit donor to a minor extent. The most powerful donor of the C-1 unit of the yellow substance in our experiments was glyxylic acid. On aerobic oxidation of 5-hydroxytryptamine with glyoxylic acid, and more so together with iron-EDTA, the yellow substance was produced at a higher rate than with formaldehyde and iron-EDTA. Anaerobic incubation of 5-hydroxytryptamine with glyoxylic acid at 60°C at alkaline pH gave another yellow compound which was identified as 2-carboxymethyl-3,4-dihydro-β-carboline ( III), on the basis of NMR and FD mass spectrometry. The borohydride-reduced compound was found to be 6-hydroxy-2-carboxymethyl-1,2,3,4-tetrahydro-β-carboline. The reduced compound was hardly autoxidizable. A common precursor for both the yellow substance and the anaerobically formed yellow compound was isolated and purified from the anaerobic incubation mixture of 5-hydroxytryptamine and glyoxylate at alkaline pH. The structure was found to be 6-hydroxy-1-carboxyl-1,2,3,4-tetrahydro-β-carboline ( IV).

Neuropharmacology of several β-carboline derivatives and their 9-acetylated esters. In vivo versus in vitro studies in the rabbit

The effects of 3-methoxycarbonyl- (beta-CCM, Ia), 3-ethoxycarbonyl- (beta-CCE, Ic), 3-propoxycarbonyl- (PrCC, Ie), 3-N-methylcarboxamido- (FG-7142, Ig) beta-carboline and 2-acetyl-3-methoxycarbonyl-1,2-dihydro-beta-carboline (IIa) as well as of their corresponding 9-acetyl derivatives (Ib, Id, If, Ih and IIb) have been studied in rabbits. In addition, the effects of 6,7-dimethoxy-4-ethyl-3-methoxycarbonyl-beta-carboline (DMCM) have also been studied. In in vitro studies, these drugs compete with 3H-diazepam to benzodiazepine (BDZ) receptor in membrane preparations from brain cortex. The values of IC50 are in the nanomolar range without significant differences between the acetyl derivatives and their congeners only compound If shows a 10-fold decrease of the binding capacity in respect to its congener Ie. In the presence of 10(-5) M GABA, a decrease in the binding capacity for DMCM, Ia, Ic and Ig and an increase for If are observed. In vivo studies show that DMCM, Ia, Ib, IIa and IIb elicit three dose-dependent stages of electrocortical changes (trains of slow waves, trains of spike-and-wave complexes and "grand-mal" seizures). Compounds Ic, Id and Ig elicit only the first two stages. Compound Ih elicits only the first stage. While compound Ie does not affect the EEG pattern, its 9-acetyl derivative If induces changes (cortical spindles and disruption of the hippocampal theta waves) characteristic of agonist ligands of BDZ receptor. These findings confirm that the efficacy of compounds DMCM, Ia, Ic, Id, Ig and Ih as inverse agonists of BDZ receptor in the EEG paradigm parallels the reduction of their apparent binding affinity in the presence of GABA. The 9-acetylated compounds may be more inverse agonist in vivo than predicted from the in vitro findings, due to hydrolysis in the plasma.

Harman and norharman induce SOS responses and frameshift mutations in bacteria

Norharman and harman, β-carboline derivatives with comutagenic activity in Salmonella typhimurium, were examined for their activity to induce SOS responses in S. typhimurium using the umu-test and mutations in Escherichia coli. The inducibility of the umuC gene by norharman and harman was assayed by measuring the levels of β-galactosidase activity in tester cells harbouring the umuC′−′lacZ fusion gene on a plasmid. In the umu-test, both norharman and harman weakly induced umuC gene expression at 25–100 and 50–150 μg/ml, respectively. In the mutation test using reversion from trpE9777 to Trp +, harman was relatively more potent than norharman in inducing the mutations. These results indicate that norharman and harman induce SOS responses as well as reversion of trpE9777 frameshift mutation in bacteria.

The abstinence syndrome in diazepam-dependent cats is precipitated by Ro 15-1788 and Ro 15-4513 but not by the benzodiazepine receptor antagonist ZK 93426

Diazepam-dependent cats were challenged with different benzodiazepine recognition site ligands 24 h after the last dose of chronic treatment with diazepam (7 mg/kg, i.p. at 08.00 and 20.00 h, for 21 consecutive days). The benzodiazepine derivatives Ro 15-4513 (a partial inverse agonist) and Ro 15-1788 (a pure antagonist), precipitated an abstinence syndrome within minutes after i.p. administration. Abstinence signs included tremors, increased muscle tone, irritability, fear, pupillary dilation and vocalizations. On the contrary, the β-carboline derivatives ZK 93426 (an antagonist) and FG 7142 (a partial inverse agonist) failed to precipitate abstinence signs in diazepam-dependent cats when given at doses that prevented the acute effects of diazepam. Our results demonstrate that the ability to induce withdrawal signs in diazepam-dependent cats strongly depends on the benzodiazepine structure of the challenge drug since β-carboline antagonists and partial inverse agonists lack this property.

Apparent dipole moments and molar volumes of β-carbolines and carbazole in dioxane solution

The apparent molecular polarization at infinite dilution, P2∞, molecular refraction, RD, dipole moment, µ2, and partial molar volume, V2°, of carbazole and some β-carboline derivatives have been determined from dielectric permittivity, specific volume, and refractive index measurements in 1,4-dioxane solutions at 25 °C. Evidence of hydrogen-bonding interaction with solvent has been found from i.r. spectroscopy and the apparent molar volumes. A relation has been found between literature pKa values of β-carboline derivatives studied in the ground state and their corresponding dipole moments in solution.

Polyclonal antibodies to agonist benzodiazepines

Benzodiazepine-binding, immunoglobulin G class antibodies have been raised in three rabbits immunised with a conjugate of kenazepine coupled to keyhole limpet haemocyanin. The antibodies were assayed by [ 3H]flunitrazepam binding, followed by adsorption onto Staphylococcus aureus cells. Measurement of the rates of association and dissociation of [ 3H]flunitrazepam binding, together with saturation analysis of equilibrium binding, revealed varying degrees of heterogeneity in the affinity constants of the three rabbit antisera (equilibrium K D values 0.18 to 4.13 nM at 20–22°). Specificity of the antibodies was investigated by testing a wide variety of compounds (at concentrations of up to 10–100 (μm) for their ability to inhibit [ 3H]flunitrazepani binding. Only benzodiazepines known to act as agonists at their receptor sites in the central nervous system (CNS) caused an inhibition of binding. The rank orders of the IC 50 values of these drugs for inhibition of [ 3H]flunitrazepam binding to IgG from two out of the three rabbits correlated significantly with that previously published for displacement of CNS receptor binding. The agonist β-carboline derivative ZK 93423, the anxiolytic cyclopyrrolones suriclone and zopiclone and the purines inosine and hypoxanthine all failed to inhibit antibody binding, supporting previous suggestions that these drugs may bind at non-benzodiazepine recognition sites on the CNS receptor. The antibodies described are expected to provide useful reagents for raising anti-idiotypic antibodies directed against the CNS receptor and for the identification and purification of possible endogenous benzodiazepine receptor agonists in the CNS.

Bidirectional changes in the consumption of food produced by β-carbolines

β-Carboline derivatives provide examples of benzodiazepine receptor ligands which span the range: full agonist-partial agonist-antagonist-partial inverse agonist-full inverse agonist. Taken together, the effects of these compounds illustrate two important principles: firstly, the bidirectionality of effects which can be achieved using benzodiazepine receptor ligands; secondly, the selectivity of effects which are produced by partial agonists. Applied to the study of feecling processes, these principles imply that both hyperphagic and anorectic effects can be generated by actions of selected ligands at benzodiazepine receptors. Furthermore, they suggest that a hyperphagic effect may occur in the absence of side-effects (e.g., sedation, muscle-relaxation), which are characteristic of classical benzodiazepines. Experimental data in support of these predictions are presented. A microstructural approach to feecling behaviour indicated that a benzodiazepine receptor agonist and an inverse agonist extend and abbreviate, respectively, the duration of individual bouts of eating. Preference for a saccharin solution was attenuated by the β-carboline inverse agonist, FG 7142, but rejection of a quinine solution was not increased. Adrenalectomy had no effect on the anorectic effect of inverse agonists.

ChemInform Abstract: Reactions with 2‐Aza‐1,3‐butadiene Derivatives. Part 1. A Novel and Particularly Easy Synthesis of Centrally Acting β‐Carboline Derivatives.

AbstractThe azabutadienes (II), prepared from (I) by a modified literature procedure (cf.

Ground and first excited electronic state interaction of FAD with some β-carboline derivatives

The spectrophotometric and thermodynamic properties of molecular complexes of flavine adenine dinucleotide (FAD) with some dihydro 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 FAD 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 fluorescence phenomena observed in FAD is related to the concentration of the dihydro β-carboline derivatives allowing the calculation of the association constants for FAD-β-carboline complexes. Thermodynamic parameters have been determined from the values of association constants for the molecular complexes at several temperatures.

β-Carbolines characterized as benzodiazepine receptor agonists and inverse agonists produce bi-directional changes in palatable food consumption

Drugs which bind to specific benzodiazepine recognition sites fall into three categories: agonists, antagonists and inverse agonists. A set of biochemical parameters is available which distinguishes between the three. In addition, actions of the drugs result in physiological and behavioural effects which are distinguishable. β-Carboline derivatives provide a group of compounds which show high affinity for the benzodiazepine sites and which contains examples belonging to each of the three categories. Evidence is reviewed which shows that β-carboline benzodiazepine receptor agonists (ZK 93423, ZK 91296) produce increases in the consumption of a palatable diet by non-deprived rats, that β-carboline inverse agonists (FG 7142, DMCM) produce an anorectic effect and that the β-carboline ZK 93426 acts as a benzodiazepine receptor antagonist. The resuks support the proposal of bi-directional control of feeding responses through the action of drugs at a common benzodiazepine receptor. Furthermore, benzodiazepine receptor inverse agonists provide a novel class of anorectic agents. Evidence is also reviewed which is suggestive of the modulation of food-related reward by drug actions at benzodiazepine receptors.

The effects of β-carboline carboxylic acid ethyl ester and its free acid, administered ICV, on the anticonvulsant activity of diazepam and sodium valproate in the mouse

The effects of intracerebroventricular (ICV) β-carboline carboxylic acid ethyl ester (β-CCE) and its free acid on the protective effects of diazepam against leptazol- and R05-3663-induced convulsions were investigated in mice and compared with their effects on the antileptazol effect of sodium valproate, in an attempt to demonstrate a specific central effect of β-CCE on benzodiazepine function. The results show that a small dose (1 μg) of β-CCE but not its free acid (in doses up to 100 μg) was able to reverse the protective effects of diazepam against leptazol- and R05-3663-induced convulsions, whereas the effects of sodium valproate, a non-benzodiazepine anticonvulsant, could not be reversed by these β-carboline derivatives.