PubMed · 1389613
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N Sarker. 1992-09-19. 'Alternatives to toothpaste'.. https://doi.org/10.1038/sj.bdj.4807981
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We report that commercially available beta-carbolines (nor-harmane (9H-pyrido[3,4-b]indole), harmane (1-methyl-9H-pyrido[3,4-b]indole), harmine (7-methoxy-1-methyl-9H-pyrido[3,4-b]indole), harmol (1-methyl-9H-pyrido[3,4-b]indol-7-ol), harmaline (3,4-dihydro-7-methoxy-1-methyl-9H-pyrido[3,4-b]indole) and harmalol (3,4-dihydro-1-methyl-9H-pyrido[3,4-b]indol-7-ol)), are useful MALDI matrices at 337 nm, for cyclic oligosaccharides (cyclodextrins, range 972-1290 Da), acyclic oligosaccharides (range 342-828 Da) and high molecular mass proteins (range 23,290-66,525 Da) in both positive and negative modes. This was investigated by using time-of-flight (TOF) mass spectrometers of different sensitivities, equipped with and without pulse extraction facilities. A comparison with conventional matrices for carbohydrates (DHB and DHB/HIC) indicates that beta-carbolines provide the same level of sensitivity and resolution in the positive mode, but offer the advantage of high levels of sensitivity and resolution in the negative mode. Harmaline has been found to be specially effective for the analysis of high-mass proteins in both modes, and also exhibits excellent experimental reproducibility of the results owing to the homogeneous crystallization of the analyte-matrix mixture over the entire sample surface area. Harmane and nor-harmane are both excellent matrices for high-mass proteins also. As MALDI matrices, beta-carbolines permit measurement of sulfated sugars in the negative ion mode as ([M-H]), and of neutral sugars and proteins as both [M + H]+ and [M-H]- in appropriate modes.
1H NMR studies were performed on two beta-carboline derivatives interacting with human serum albumin. The spin-lattice relaxation rates of the two derivatives, having side chains of different length and polarity, were used to demonstrate a diverse motional behavior in solution together with slightly different relaxation pathways. Single- and double-selective excitation made it possible to evaluate dynamics in the free and protein-bound states. Occurrence of a relatively long hydrophilic chain interacting with the proton-acceptor nitrogen of the beta-carboline moiety was shown to yield lower association constants, slower dissociation rates, and diverse interacting modes with the indole hydrophobic site of the protein.
Naturally occurring beta-carbolines are lipophilic compounds which show psychotropic and physiological effects in mammals. They bind to distinct high-affinity binding sites in various mammalian tissues. However, the mechanism by which the beta-carbolines affect transmembrane signal transduction processes is still unknown. Since beta-carbolines are cationic-amphiphilic substances and since such substances are known to activate heterotrimeric regulatory guanine nucleotide binding proteins (G-proteins) in a receptor-independent manner, we put forward the hypothesis that beta-carbolines act directly on G-proteins. Therefore, we investigated the ability of beta-carbolines to stimulate high-affinity GTP hydrolysis in membranes of dibutyryl-cAMP differentiated HL-60 cells and of the purified bovine G-protein, transducin (TD). The beta-carbolines norharman and harman, stimulated the GTPase in HL-60 membranes with an EC50 of 410 microM and 450 microM, respectively, and a maximum effect at 1 mM each. Norharman and harman stimulated the GTPase of TD with an EC50 of 60 microM and 300 microM, and a maximum at 1 mM for both compounds. The stimulatory effect of norharman in HL-60 membranes was pertussis toxin-sensitive. Structure/activity characteristics of the beta-carbolines showed a specificity of norharman to stimulate the GTPase of TD, because norharman activated GTP hydrolysis in HL-60 membranes approximately 7 times less potently than that of TD. Norharman was a five-fold more potent activator of TD than tetrahydronorharman. Hydroxylation of the beta-carboline molecule in position 6 led to a loss of GTPase-activating properties. Our data suggest that naturally occurring beta-carbolines are a novel class of receptor-independent G-protein activating substances. This mechanism could contribute to their diverse biological effects.