Modelling the binding step in dopamine receptor–antagonist interactions

Boudon, Alain; Szymoniak, Jan; Chrétien, Jacques R.; Dubois, Jacques-Émile

doi:10.1139/v88-465

Cited by 3 publications

(1 citation statement)

References 8 publications

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“…The interaction of frontier orbitals (HOMO, highest occupied molecular orbital and LUMO, lowest unoccupied molecular orbital) has been shown to play a role in chemical reactivity (Chan et al, 2007a;Osman et al, 1988). Generally, HOMO of the nucleophile reacts with the LUMO of the electrophilic species (Lewis, 1999), where LUMO typically acts as an electron acceptor in chargetransfer interactions (Boudon et al, 1988). Previous work from our laboratory showed that E LUMO was also a good descriptor for hepatotoxic effects for a series of pbenzoquinones which are also electrophilic compounds that act via Michael-type mechanism (Chan et al, 2007a).…”

Section: Discussionmentioning

confidence: 99%

Structure–activity relationships for hepatocyte toxicity and electrophilic reactivity of α,β‐unsaturated esters, acrylates and methacrylates

Chan

O’Brien

2008

J of Applied Toxicology

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Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, electrophile reactivity towards biological nucleophiles could serve as an important correlate for toxic effects such as hepatocyte death. To determine if reactivity correlates with rat hepatotoxicity, alpha,beta-unsaturated esters, consisting of acrylates and methacrylates, that are inherently electrophilic and exhibit widely varying degrees of reactivity were investigated. Reactivity was measured using simple assays with glutathione and butylamine as surrogates for soft thiol and hard amino biological nucleophile targets. A linear relationship was observed between hepatotoxicity and thiol reactivity only, while no amine reactivity was observed. Structure-activity relationships were also investigated, with results showing toxicity was well modeled by electronic parameters E(LUMO) and partial charge of the carbon atoms in the reactive center. No relationship was observed between toxicity and logP. These results suggest that differences in hepatocyte toxicity of acrylates and methacrylates can be related to their electrophilic reactivity which corresponds to their ability to deplete GSH and protein thiols.

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Section: Discussionmentioning

confidence: 99%

Structure–activity relationships for hepatocyte toxicity and electrophilic reactivity of α,β‐unsaturated esters, acrylates and methacrylates

Chan

O’Brien

2008

J of Applied Toxicology

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1,2‐Benzisoxazoles

Gualtieri

Giannella

1999

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Nitrogen radical cations as intermediates in enzymatically mediated oxidative deaminations?application of molecular parametric models

Huang

Doerge

Bodor

et al. 1995

Int. J. Quantum Chem.

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rnExperimentally measured rates for the oxidation of p-substituted benzyl amines by bovine monoamine oxidase type B (MAO-B) derived from the literature were examined with respect to the effects of molecular (semiempirically AM^) derived) electronic, steric, and lipophilicity parameters. These properties included vertical and adiabatic ionization potential, LUMO energy, the LUMO-HOMO difference, molecular hardness, absolute electronegativity, calculated log P values, molecular volume, surface area, and ovality. Substrate oxidation rates (log kcat/KnE) were found to correlate with molecular ovality and vertical ionization potential while the rate of enzymatic (flavin) reduction associated with substrate oxidation (log kred) was described by a two-parameter model containing an ovality and an absolute electronegativity term. These results are consistent with an initial one-electron substrate oxidation mechanism. In previous work, use of classical Hansch analysis suggested that electronic terms were not important in the enzymatic reactions. This discrepancy may be related to nontransferability inherent in fragment approaches which assume that the substituent of interest behaves similarly in all molecular scaffolds. Analysis of substrate binding (log K L j ) to the enzyme was described by a two-parameter model containing a calculated log P term as well as LUMO energy. The significant correlation found with LUMO energy is consistent with studies suggesting that this property is important for drug-receptor interactions.

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Modelling the binding step in dopamine receptor–antagonist interactions

Cited by 3 publications

References 8 publications

Structure–activity relationships for hepatocyte toxicity and electrophilic reactivity of α,β‐unsaturated esters, acrylates and methacrylates

Structure–activity relationships for hepatocyte toxicity and electrophilic reactivity of α,β‐unsaturated esters, acrylates and methacrylates

1,2‐Benzisoxazoles

Nitrogen radical cations as intermediates in enzymatically mediated oxidative deaminations?application of molecular parametric models

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