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P A Carrupt

Publications and source records attributed to P A Carrupt.

16 recordsLinked to original sources
PubMed1991

Partitioning of solutes in different solvent systems: the contribution of hydrogen-bonding capacity and polarity.

Published partition coefficient values of 121 solutes in five solvent systems (1-octanol-water, n-heptane-water, chloroform-water, diethyl ether-water, and n-butyl acetate-water) were correlated with solute properties, namely intrinsic molecular volume (indicator of cavity formation) and the solvatochromic parameters pi* (dipolarity/polarizability), beta (H-bond acceptor basicity), and alpha (H-bond donor acidity). While the cavity term and the H-bond accepting capacity played a comparable role in all solvent systems, the H-bond donor acidity was significant only in the alkane-water and chloroform-water systems. Comparison of the regression coefficients of pi*, beta, and alpha demonstrated the important role that water content at saturation in the organic solvents plays in the partitioning of solutes. Analysis of the differences between 1-octanol-water and n-heptane-water partition coefficients (delta log Poct-hep) and between 1-octanol-water and chloroform-water partition coefficients (delta log Poct-chf) showed that these values mainly quantitate the capacity of solute to donate hydrogen bonds. In contrast, the differences between 1-octanol-water and diethyl ether-water or n-butylacetate-water partition coefficients, (delta log Poct-dee and delta log Poct-ba, respectively) contain no structural information.

Chemical Phenomena↗
PubMed1991

Percutaneous penetration of drugs: a quantitative structure-permeability relationship study.

Human skin permeation data taken from the literature were analyzed for quantitative relationships with physicochemical properties and structural descriptors. No correlations exist with molecular weights and solvent-accessible surface areas. In most cases, skin permeation was inversely correlated with the parameter delta log Poct-hep (i.e., log Poctanol minus log Pheptane), which is mainly a measure of the H-bond donor acidity of the solutes. Lipophilicity itself, as expressed by log Poctanol, also contributes positively to skin permeation in some cases. The results of this quantitative structure-permeability relationship study are interpreted in terms of a unified mechanistic model whereby drugs can permeate via an intercellular route (correlation with both delta log Poct-hep and log Poct) and/or a transcellular route (correlation with log Poct only).

Administration, Topical↗
PubMed1991

Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity.

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membranes.

Calorimetry↗
PubMed1990

Toxication of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and analogs by monoamine oxidase. A structure-reactivity relationship study.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits motor deficits similar to those observed in Parkinson's disease. Before exerting its neurotoxic action, MPTP must be activated by brain monoamine oxidase (MAO) to the neurotoxic metabolite MPP+ (1-methyl-4-phenylpyridinium). MPTP derivatives differ in their reactivity as MAO substrates and in their neurotoxicity. A structure-reactivity relationship study based on literature data was undertaken in order to determine the key features in the structure of MPTP and analogs that are responsible for the reactivity towards MAO. Thirty-three MPTP derivatives (including MPTP itself) were included in the study. To explain the reactivity towards MAO of the 33 MPTP analogs, different statistical methods (principal component analysis, multiple linear regression analysis) as well as the CoMFA (Comparative Molecular Field Analysis) approach, a new tool in structure-activity correlations, were used. Linear regression analysis failed to yield any predictive model, but suggested some trends. In contrast, the CoMFA approach was successful in correlating structural features and MAO reactivity. Coefficient contour maps showed where differences in the steric field (van der Waals' interactions) are most highly associated with differences in MAO reactivity. Several positive (in the ortho- and meta-position of the phenyl group) and negative (in the para-position of the phenyl group; beyond the N-methyl group) interaction regions were identified. Some structural features of the MAO active site could be postulated. First, the N-methyl group has the ideal size and elicits ideal interactions within the MAO active pocket, while smaller or larger groups are less favorable; second, para-substituent on the phenyl ring produce steric hindrances and are unfavorable to reactivity; third, ortho- and meta-substituents may have stabilizing interactions within the active pocket and are favorable to the reactivity. Moreover the model derived by CoMFA allowed us to make successful predictions of reactivity towards MAO for several additional tetrahydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Pattern recognition study of QSAR substituent descriptors.

Parameter values for 59 common substituents and 74 descriptors used in QSAR studies were compiled. This data matrix was analysed by a variety of multivariate techniques. Linear regression confirmed that lipophilicity can be factorized into two terms, one related to molecular bulk and the other to polarity. Principal component analysis (PCA) of parameters revealed 5 significant principal components and a grouping of lipophilic, steric and electronic parameters. The different loadings of parameters with 5 PCA were also explored. The classification of substituents by cluster analysis (CA) proved rather disappointing. In contrast, the SIMCA method classified substituents of increasing bulk into 5 groups of increasing polarity.

Analysis of Variance↗
PubMed1989

Stereoelectronic study of zetidoline, a dopamine D2 receptor antagonist.

A combination of experimental and theoretical methods were used to investigate the stereoelectronic structure of zetidoline, a dopamine D2 receptor antagonist showing Na+-dependent binding. The solid-state conformation of zetidoline is characterized by synplanarity (coplanarity of the two rings with the chloro substituent and the carbonyl group on the same side). The side chain in the crystal adopts a folded conformation which places the azetidine nitrogen atom at about 8 A from the center of the aromatic ring. Quantum mechanical calculations indicate the synperiplanar and antiperiplanar conformations of the ring system to be of approximately equal energies. The molecular electrostatic potential of zetidoline in a nearly extended conformation shows a remarkable similarity with that of orthopramides (e.g. metoclopramide) and indolones (e.g. piquindone), i.e. two groups of drugs displaying the same D2 selectivity and Na+-dependent binding. We postulate that the close stereoelectronic similarity between zetidoline, orthopramides, and indolones accounts for their identical mechanism of action in the molecular level.

Chemical Phenomena↗
PubMed1988

Modeling of beta-adrenoceptors based on molecular electrostatic potential studies of agonists and antagonists.

The molecular electrostatic potential (MEP) of 32 beta-adrenoceptor ligands, mainly antagonists, was calculated by the STO-3G ab initio quantum mechanical method. The MEP of phenylethanolamines (PEAs) features a negative minimum in the meta region (designated M1) which is topographically equivalent to a minimum (designated M2) found in the vicinity of the aromatic ring in all (aryloxy)propanolamines (AOPAs). In these compounds, a second negative zone located beyond the meta position and designated M3 is found in all beta 1-selective antagonists and in some nonselective and beta 2-selective antagonists. The beta 1-selective antagonists feature in the para position an additional zone which is positive (P4) in the full antagonists and negative (M4) in the antagonists displaying intrinsic sympathomimetic activity (ISA). The MEP-based pharmacophoric models of PEAs, AOPAs, and oxime ethers show common elements and lead to a proposed general model for beta-adrenoceptor ligands.

Adrenergic beta-Agonists↗
PubMed1988

Influence of lipophilicity and chirality on the selectivity of ligands for beta 1- and beta 2-adrenoceptors.

Eudismic and QSAR analyses are reported for the beta 1- and beta 2-adrenoceptor affinities and beta 1-selectivity of 10 enantiomeric pairs of ligands with only N-isopropyl or N-t-butyl groups. For both receptors, the eudismic index (ratio of affinity) increases with the affinity of the eutomers. However, the affinity of the distomers for the beta 2-adrenoceptor is relatively high, suggesting additional hydrophobic interactions. This is confirmed by various correlations between affinities and lipophilicities, showing that the affinity for beta 2-adrenoceptors is slightly more dependent on lipophilicity than that for beta 1-adrenoceptors. As a result, the beta 1-selectivity of the investigated beta 1-adrenoceptor ligands is strongly and negatively correlated with their lipophilicity (r = -0.942).

Adrenergic beta-Agonists↗
PubMedDate not supplied

Quantitative structure-metabolism relationship analyses of MAO-mediated toxication of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analogues.

The 1-octanol/water partition coefficients of a number of toxic and nontoxic analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were determined using centrifugal partition chromatography (CPC), a novel and effective technique for measuring lipophilicity, and found to be highly correlated with values calculated by a fragmental method. Some conformational properties of these compounds were also assessed by molecular mechanics calculations and 1H-NMR spectroscopy. A quantitative structure-metabolism relationship (QSMR) study of MPTP and analogues based on literature data was undertaken in order to determine the key features eliciting MAO-A and MAO-B reactivity and selectivity and influencing toxication. Multiple regression analysis (MRA) and comparative molecular field analysis (CoMFA) showed that MAO-B activity is nonlinearly (parabolically or bilinearly) correlated to the lipophilicity of MPTP analogues and influenced negatively by steric effects exerted by bulky substituents in the ortho position. With regard to MAO-A activity, while lipophilicity was shown to play no relevant role, electrostatic and steric fields led to a 3D-QSAR model with an acceptable predictive value (cross-validated r2 = 0.571). The results of this study bring evidence at a quantitative level that the MAO-B and MAO-A catalytic sites differ in their hydrophobic, steric, and stereoelectronic requirements.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗