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  • 1
    Electronic Resource
    Electronic Resource
    Differential Cytotoxicities of N-Methyl-β-Carbolinium Analogues of MPP+ in PC12 Cells: Insights into Potential Neurotoxicants in Parkinson's Disease (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 62 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: N-Methylated β-carbolinium cations that can form in vivo from environmental or endogenous β-carbolines are putative neurotoxic factors in Parkinson's disease. The cytotoxicities of 11 N-methylated β-carbolinium cations and N-methyl-4-phenylpyridinium cation (MPP+), the experimental parkinsonian neurotoxicant which the carbolinium cations structurally resemble, were examined using rat pheochromocytoma (PC12) cells cultured in “low energy” N-5 medium; cell death was estimated by released lactate dehydrogenase activity and viable cell protein. Of the eight N-monomethylated β-carbolinium cations utilized, only 2-methyl-harmalinium (harmaline-2- methiodide) was as cytotoxic as MPP+. Also, three N2(β), N8(indole)-dimethylated β-carbolinium cations displayed cytotoxic effects, with the simplest, 2,9-dimethylnorhar- manium, approaching the effectiveness of MPP+ in PC12 cells cultured in N-5 medium. However, when PC12 cells grown in higher energy Dulbecco's modified Eagle's medium were utilized with selected effective cations, it was observed that the cultures were relatively resistant to MPP+ and 2,9-dimethylnorharmanium, but remained vulnerable to 2-methylharmalinium. The results are interpreted to mean that different cytotoxic mechanisms exist for the two most potent β-carbolinium cations—namely, a mechanism for the 2,9-dimethyl-β-carbolinium species that, as with MPP+, is conditional on mitochondrial ATP depletion, but a different (or additional) mechanism for 2- methylharmalinium that is independent of mitochondrial inhibition. The possible accumulation of these cytotoxic cations in Parkinson's disease is discussed in the context of these findings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.62041503.x
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  • 2
    Electronic Resource
    Electronic Resource
    Brain and Plasma Tetrahydroisoquinolines in Rats: Effects of Chronic Ethanol Intake and Diet (1990)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 55 (1990), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Brain concentrations of salsolinol (SAL), a simple tetrahydroisoquinoline (sTIQ) condensation product of do-pamine (DA) and acetaldehyde, are reported to increase in chow-fed rats drinking ethanol/H2O ad libitum. However, our analyses showed that rat chow contains traces of SAL and, as previously reported, appreciable 3,4-dihydroxyphe-nylalanine (DOPA), a sTIQ precursor. To examine the effect of consumption of ethanol in a DOPA- and SAL-free diet on endogenous sTIQs, we analyzed two brain regions and blood plasma of rats undergoing prolonged intake (3 weeks and 23 weeks) of liquid diet containing 6.6% ethanol or iso-caloric carbohydrate. SAL and three other DA-related sTIQs were quantitated using capillary gas chromatography/mass spectrometry in the selected ion mode with deuterated standards. In accord with studies on ethanol/chow-fed rats. sTIQ concentrations in hypothalamus were elevated after 3 weeks of ethanol, although after 23 weeks, hypothalamic sTIQs were either unchanged or reduced (O-methylated SAL). Furthermore, sTIQ concentrations in corpus triatum and, with one exception, plasma were not altered by ethanol ingestion for either duration. (However, 23 weeks of ethanol intake significantly reduced the striatal concentrations of DA and its acid metabolite, presumably reflecting neurotoxicity.) Reasoning that DOPA in diet might underlie the reported ethanol-dependent increases in striatal sTIQs, we found that l-DOPA supplementation (500 μg/rat/day) of EtOH/Iiquid diet-fed rats for 13 weeks tended to increase striatal SAL. Overall, the data indicate that elevations in endogenous sTIQ concentrations due to prolonged ethanol intake depend on the brain region, duration of intake, and even associated dietary constituents. In that regard, the higher striatal SAL concentrations in rats drinking ethanol ad libitum could have been facilitated by DOPA and perhaps SAL consumed in lab chow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1990.tb04932.x
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  • 3
    Electronic Resource
    Electronic Resource
    Mono-N-Methylation of 1,2,3,4-Tetrahydro-β-Carbolines in Brain Cytosol: Absence of Indole Methylation (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 59 (1992), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: In an accompanying report we demonstrated enzyme activity in guinea pig brain cell nuclei that catalyzes S-adenosylmethionine (SAM)-dependent N-methylations of heteroaromatic β-carbolines (BCs) on the 2[β]-nitrogen and subsequently on the 9[indole]-nitrogen, ultimately yielding N2,N9-dimethylated BCs. Presented here are the esults of a parallel study of the N-methylation of 1,2,3,4-tetrahydro-BCs (THBCs), which form endogenously via condensations of tryptophan and its derived indoles with carbonyl compounds or, like their BC oxidation products, are environmental constituents and plant alkaloids. THBCs were enzymatically methylated on the 2[β]-nitrogen by [3H]-SAM in undialyzed homogenates of rat or guinea pig brain, but [3H]methyl transfer to the 9[indole]-nitrogen was not observed. The structure of the 2[β]-methyl THBC product was verified with capillary gas chromatography-mass spectrometry. Furthermore, whereas BC N-methylation was largely particulate and displayed micromolar Km values for BC substrate, THBC 2[β]-N-methylation activity was cytosolic and displayed a relatively high (millimolar) Km for THBC substrate. The N-methylation of THBCs may be due to cytosolic N-methyltransferases that others have studied using different azaheterocyclics. Our overall studies indicate that N2,N9-dimethylated BCs could be unique neurotoxic factors that are bioactivated within brain by sequential N-methylations of BCs. These results suggest the possibility of an additional route to the putative 2,9-dimethylated toxins involving, as a first step, 2[β]-N-methylation of environmental or endogenously derived THBCs in the brain and perhaps other organs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1992.tb09399.x
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  • 4
    Electronic Resource
    Electronic Resource
    Novel S-Adenosylmethionine-Dependent Indole-N-Methylation of β-Carbolines in Brain Particulate Fractions (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 59 (1992), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Guinea pig brain S-adenosylmethionine (SAM)-dependent N-methyltransferase activity toward physiologically relevant β-carboline (BC) substrates was examined with reverse-phase HPLC and radiochemical detection. Representative BCs, norharman and harmine, were enzymatically methylated on the 2[β]-nitrogen by [3H]CH3-SAM in undialyzed homogenates to yield 2[β]-methylated BCs and subsequently on the 9[indole]-nitrogen to generate 2,9-dimethylated BC products. This may be the first account of mammalian indole N-methyl transfer. There was no HPLC evidence for 9-methyl BC or (from carbon methylation) 2,6-dimethyl BC products. Capillary gas chromatography-mass spectrometry analysis confirmed the structures of the 2,9-dimethyl and 2-methyl products of norharman. The 2[β]- and 9[indole]-N-methylation activities were mainly in the nuclear fractions and were negligible in undialyzed cytosol. This differs from the cytosolic SAM-dependent N-methylations reported with other azaheterocyclics, including 1,2,3,4-tetrahydro-BCs. The involvement of a single enzyme was suggested because the two N-methyl transfers with BC substrate had similar subcellular activity patterns, regional brain distributions, and Km and Vmax values. Sequential N-methylation of various BCs that have been observed in vivo may be a unique route to centrally retained N2,N9-dimethylated β-carbolinium ions. Because they resemble the synthetic parkinsonian toxicant, N-methyl-4-phenylpyridinium, with respect to structure and neurotoxic activity, such “bioactivated” carbolinium ions could be endogenous causative factors in Parkinson's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1992.tb09400.x
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  • 5
    Electronic Resource
    Electronic Resource
    Inhibition of Catechol-O-Methyltransferase by 6,7-Dihydroxy-3,4-Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O-Methylation (1987)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 48 (1987), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We report that 6,7-dihydroxy-3,4-dihydroisoquinolines related to dopamine are potent inhibitors of catechol-O-methyltransferase (COMT), but are not apparent substrates for the enzyme in vitro or in vivo. Three dihy-droxy (catecholic) dihydroisoquinolines, including the 1-benzyl (DesDHP) and the 1-methyl (DSAL) analogs, were found to inhibit COMT activity in rat liver supernatant more effectively than the well-known inhibitor, tropolone. Inhibition of O-methylation was uncompetitive with substrate, and O-methylated products of the catecholic dihydroisoquinolines were undetectable. For these in vitro studies, a facile liquid chromatographic assay was developed utilizing as a site-specific substrate, 1-methyl-6,7-dihydroxy-tetrahydroisoquinoline-1 -carboxylate (salsolinol-1-carboxylate). This catechol produces only one phenolic product isomer when incubated with liver supernatant and S-adenosylmethionine. Following central injection of DSAL in rats, inhibition of brain COMT in vivo was indicated by the reduced brain levels of homovanillic acid, but not of 3,4-dihydroxyphenylacetic acid. Furthermore, O-methylated DSAL metabolites could not be detected in brain by liquid or gas chromatography. We suggest that 6,7–dihydroxy-dihydroisoquinolines are “nonmethylatable” COMT inhibitors because they exist as quinoidal tautomers resembling pyridones or tropolones rather than as catechols. Quinoid formation is supported by the fluorescence and ultraviolet spectra for DSAL and its O-methyl derivatives. The experiments reveal a new class of COMT inhibitors that may be of pharmacological and mechanistic value. Additionally, 3,4-dihydroisoquinolines could arise endogenously via oxidation of the 1,2,3,4-tetrahydroisoquinolines which are ingested or produced from cellular catecholamine condensations. However, it is unlikely that dihydroisoquinoline (e.g., DSAL) concentrations necessary to inhibit COMT significantly would be attained via endogenous pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1987.tb05585.x
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  • 6
    Electronic Resource
    Electronic Resource
    Application of interpolated potential energy surfaces to quantum reactive scattering (1999)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 111 (1999), S. 9924-9931 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: The accuracy of an interpolation approach to molecular potential energy surfaces for quantum reactive scattering is demonstrated by comparison of the quantum reaction probability for a model surface and its interpolated approximation. Effective convergence of an ab initio surface with the size of the interpolation data set is demonstrated for the reaction BeH+H2 → BeH2+H. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.480344
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  • 7
    Electronic Resource
    Electronic Resource
    Interpolated potential energy surface and reaction dynamics for O(3P)+H3+(1A1′) and OH+(3Σ−)+H2(1Σg+) (1999)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 111 (1999), S. 6322-6332 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: An ab initio potential energy surface for the triplet state of OH3+ has been constructed at the MP2/6-311G(2d,p) level of theory. Classical simulations of the title collisions have been carried out to evaluate the rate coefficients for three reactions, including H3++O→H2O++H. Examination of the singlet-triplet energy gap across the triplet surface has shown no evidence for significant surface crossing effects on the dynamics. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.479937
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  • 8
    Electronic Resource
    Electronic Resource
    Interpolated potential energy surface and dynamics for the reactions between N(4S) and H3+(1A1′) (1998)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 109 (1998), S. 9728-9736 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: An ab initio potential energy surface for the quartet electronic state of NH3+ has been constructed at the MP2/6-31G(d,p) level of theory. The accuracy of this surface has been verified by comparison with high levels of theory. Classical simulations of the collision of N(4S) and H3+(1A1′) showed no reaction to form NH2++H at thermal energies. The possibility of reaction via surface hopping to the doublet electronic state has been investigated by calculation of the quartet–doublet energy gap at the MRCI/6-311+G(2df,p) level of theory. No evidence of surface crossing could be found for configurations accessible at thermal energies. © 1998 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.477643
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  • 9
    Electronic Resource
    Electronic Resource
    Construction of interpolated potential energy surfaces using constrained dynamics: Application to rotational inelastic scattering (1999)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 111 (1999), S. 1346-1353 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: An established method for constructing molecular potential energy surfaces by interpolation of ab initio data has been coupled with a new approach to sampling molecular configurations which uses constrained classical dynamics. To illustrate this approach, model surfaces for the scattering of two rigid diatomic molecules are derived and shown to accurately predict rotational inelastic scattering cross sections. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.479393
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  • 10
    Electronic Resource
    Electronic Resource
    Learning to interpolate molecular potential energy surfaces with confidence: A Bayesian approach (1999)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 111 (1999), S. 816-826 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: A modified form of Shepard interpolation of ab initio molecular potential energy surfaces is presented. This approach yields significant improvement in accuracy over previous related schemes. Here each Taylor expansion used in the interpolation formula is assigned a confidence volume which controls the relative weight assigned to that expansion. The parameters determining this confidence volume are derived automatically from a simple Bayesian analysis of the interpolation data. As the iterative scheme expands the data set, the confidence volumes are also iteratively refined. The potential energy surfaces for nine reactions are used to illustrate the accuracy obtained. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.479368
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