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P A Carrupt

Publications and source records attributed to P A Carrupt.

At least 19 recordsLinked to original sources
PubMed2000

Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs.

A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.

Animals↗
PubMed2000

Predicting blood-brain barrier permeation from three-dimensional molecular structure.

Predicting blood-brain barrier (BBB) permeation remains a challenge in drug design. Since it is impossible to determine experimentally the BBB partitioning of large numbers of preclinical candidates, alternative evaluation methods based on computerized models are desirable. The present study was conducted to demonstrate the value of descriptors derived from 3D molecular fields in estimating the BBB permeation of a large set of compounds and to produce a simple mathematical model suitable for external prediction. The method used (VolSurf) transforms 3D fields into descriptors and correlates them to the experimental permeation by a discriminant partial least squares procedure. The model obtained here correctly predicts more than 90% of the BBB permeation data. By quantifying the favorable and unfavorable contributions of physicochemical and structural properties, it also offers valuable insights for drug design, pharmacological profiling, and screening. The computational procedure is fully automated and quite fast. The method thus appears as a valuable new tool in virtual screening where selection or prioritization of candidates is required from large collections of compounds.

Blood-Brain Barrier↗
PubMed2000

[Chirality and drugs].

The two enantiomers of a chiral drug may have vastly different pharmacodynamic and pharmacokinetic properties. As a result, the research and development of chiral drugs raises specific problems some of which are discussed here. Thus, various pharmacokinetic interactions may involve two enantiomers, as seen for example when one enantiomer inhibits the metabolism of the other and modifies its effects. A different situation occurs when a third compound stereoselectively inhibits the metabolism of one of the two enantiomers. Another problem examined here results from the lack of configurational stability of some chiral drugs, a little known phenomenon whose consequences can be of pharmacological or pharmaceutical significance depending on the rate of the reaction of racemization or epimerisation. In-depth investigations are needed before choosing between a eutomer or a racemate.

Drug Therapy↗
PubMed2000

Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation.

Clopidogrel hydrogen sulfate, a thienopyridine derivative, is an ADP receptor antagonist that inhibits platelet aggregation. Clopidogrel is an enantiopure carboxylic ester of S-configuration. The R-enantiomer is devoid of antithrombotic activity and can provoke convulsions at high doses in animals. During preclinical safety evaluation, the possible chiral inversion of clopidogrel has, therefore, been investigated in vivo after repeated oral administration of different dose levels of clopidogrel to male and female rats. Due to rapid metabolism in the liver and low plasma levels of unchanged drug, possible chiral inversion was assessed by monitoring the plasma concentrations of the carboxylic acid metabolites, i.e., the (S)- and (R)-acid, by means of a stereoselective assay. The production of 4 to 8% of (R)-acid was observed. This could be the result of chiral inversion of either clopidogrel or its main metabolite, the (S)-acid. Thus, the possibility of nonenzymatic and enzymatic inversion of clopidogrel and its carboxylic acid metabolite was studied in vitro by chiral HPLC and (1)H NMR. Nonenzymatic chiral inversion of clopidogrel at 37 degrees C in 0.1 M phosphate buffers could be observed but was found to be slow, with estimated half-lives of 7 to 12 days, depending on the pH. The (S)-acid was configurationally fully stable up to 45 days in phosphate buffers. Neither clopidogrel nor its carboxylic acid metabolites were subject to enzymatic chiral inversion in isolated rat hepatocyte suspensions. We conclude that the nonenzymatic inversion of clopidogrel accounts for the 4 to 8% of chiral inversion seen in vivo in the rat.

Algorithms↗
PubMed1999

Production and characterization of 22 monoclonal antibodies directed against S 20499, a new potent 5-HT1A chiral agonist: influence of the hapten structure on specificity and stereorecognition.

PURPOSE: An immunoconjugate model was proposed to produce stereoselective monoclonal antibodies (MAbs) for the quantitation of a 5-HT1A agonist, S 20499. MAbs produced were characterized in terms of stereoselectivity and specificity towards the opposite enantiomer and structural analogs. METHODS: The immunogen was formed following the effective addition of a butanoic acid spacer arm between the parent S 20499 structure and bovine serum albumin (BSA). After fusion (modified Köhler and Milstein's procedure), specificity of MAbs was obtained using the Abraham's criteria. Experimental and calculated partition coefficients were determined. RESULTS: Twenty-two hybridoma cell lines were established secreting MAbs (apparent association constants ranging from 1.1 x 10(8) to 2.8 X 10(9) M(-1)). Several MAbs showed cross-reactivity levels of less than 5% with S 20500 (optical antipode), which could allow a stereospecific assay to be set up. Both chroman and azaspiro moieties were part of the epitopic site. Dealkylation and hydroxylation(s) led to various crossreactivity levels. Four antibody families were described in terms of specificity. CONCLUSIONS: This study highlighted the influence of the immunoconjugate construction (coupling site and type of spacer arm) in the immuno-stereospecificity of Abs. The results obtained for two monohydroxylated metabolites suggest that the lipophilicity behavior could be a valuable tool for predicting Ab-crossreactivity.

Animals↗
PubMed1999

The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis.

PURPOSE: The anti-ischemic drug trimetazidine (TMZ) acts by a combination of molecular mechanisms which begin to be understood. Thus, it acts in the micromolar range to significantly reduce intracellular acidification during ischemia. To search for a possible physicochemical explanation of this phenomenon, we investigated the transfer mechanisms of the various electrical forms of this dibasic drug. METHODS: The transfer characteristics of TMZ were studied by electrochemistry at the water/1,2-dichloroethane interface. Cyclic voltammetry was used to measure the formal transfer potentials of singly and doubly protonated forms of TMZ (noted TH+ and TH(2)2+, respectively) as a function of aqueous pH, and the partition coefficient of neutral TMZ (log P(T)) was measured by two-phase titration. RESULTS: log P(T) was measured to be 1.04 +/- 0.06, and the acid-base dissociation constants in water were deduced to be pK(w)a1 = 4.54 +/- .02 and pK(w)a2 = 9.14 +/- 0.02. The partition coefficients of TH+ and TH(2)2+ were found to be respectively log P0'TH+ = -3.78 +/- 0.16 and log P0'TH(2)2+ = -9.84 +/- 0.30, which agrees well with the charge being delocalized on two nitrogen atoms in TH+. The pH-partition profile of TMZ was then established in the form of its ionic partition diagram, which showed that the affinity of the ions for the organic phase is pH-dependent and strongly increased by the interfacial potential. CONCLUSIONS: This behavior suggests a physicochemical mechanism whereby efflux of protonated TMZ out of an acidified cell is facilitated, in effect exporting protons to extracellular space.

Acid-Base Equilibrium↗
PubMed1999

Evaluation and prediction of drug permeation.

A major challenge confronting the pharmaceutical scientist is to optimize the selective and efficient delivery of new active entities and drug candidates. Successful drug development requires not only optimization of specific and potent pharmacodynamic activity, but also efficient delivery to the target site. Following advances in rational drug design, combinatorial chemistry and high-throughput screening techniques, the number of newly discovered and promising active compounds has increased dramatically in recent years, often making delivery problems the rate-limiting step in drug research. To overcome these problems, a good knowledge of the pharmacokinetic barriers encountered by bioactive compounds is required. This review gives an overview of the properties of relevant physiological barriers and presents some important biological models for evaluation of drug permeation and transport. Physicochemical determinants in drug permeation and the relevance of quantitative and qualitative approaches to the prediction and evaluation of passive drug absorption are also discussed.

Animals↗
PubMed1998

Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease.

The cause of neurodegeneration in Parkinson's disease (PD) remains unknown. However, isoquinoline derivatives structurally related to the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinim (MPP+), have emerged as candidate endogenous neurotoxins causing nigral cell death in Parkinson's disease. Isoquinoline derivatives are widely distributed in the environment, being present in many plants and foodstuffs, and readily cross the blood-brain barrier. These compounds occur naturally in human brain where they are synthesized by non-enzymatic condensation of biogenic amines (e.g. catecholamines and phenylethylamine) with aldehydes, and are metabolized by cytochrome P450s and N-methyltransferases. In addition, isoquinoline derivatives are oxidized by monoamine oxidases to produce isoquinolinium cations with the concomitant generation of reactive oxygen species. Neutral and quaternary isoquinoline derivatives accumulate in dopaminergic nerve terminals via the dopamine re-uptake system, for which they have moderate to poor affinity as substrates. Several isoquinoline derivatives are selective and more potent inhibitors of NADH ubiquinone reductase (complex I) and alpha-ketoglutarate dehydrogenase activity in mitochondrial fragments than MPP+, and lipophilicity appears to be important for complex I inhibition by isoquinoline derivatives. However, compared with MPP+, isoquinoline derivatives are selective but less potent inhibitors of NADH-linked respiration in intact mitochondria, and this appears to be a consequence of their rate-limiting ability to cross mitochondrial membranes. Although both active and passive processes are involved in the accumulation of isoquinoline derivatives in mitochondria, inhibition of respiration is determined by steric rather than electrostatic properties. Compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPP+, isoquinoline derivatives show selective but relatively weak toxicity to dopamine-containing cells in culture and following systemic or intracerebral administration to experimental animals, which appears to be a consequence of poor sequestration of isoquinoline derivatives by mitochondria and by dopamine-containing neurones. In conclusion, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-like cytotoxic characteristics of isoquinoline derivatives and the endogenous/environmental presence of these compounds make it conceivable that high concentrations of and/or prolonged exposure to isoquinoline derivatives might cause neurodegeneration and Parkinson's disease in humans.

Animals↗
PubMed1998

Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: effects of lipophilicity and structure-activity relationships.

A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity.

Animals↗
PubMed1998

Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants.

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.

Antioxidants↗
PubMed1998

Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist.

The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.

Alkanes↗
PubMed1998

Chiral inversion and hydrolysis of thalidomide: mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites.

The chiral inversion and hydrolysis of thalidomide and the catalysis by bases and human serum albumin were investigated by using a stereoselective HPLC assay. Chiral inversion was catalyzed by albumin, hydroxyl ions, phosphate, and amino acids. Basic amino acids (Arg and Lys) had a superior potency in catalyzing chiral inversion compared to acid and neutral ones. The chiral inversion of thalidomide is thus subject to specific and general base catalysis, and it is suggested that the ability of HSA to catalyze the reaction is due to the basic groups of the amino acids Arg and Lys and not to a single catalytic site on the macromolecule. The hydrolysis of thalidomide was also base-catalyzed. However, albumin had no effect on hydrolysis, and there was no difference between the catalytic potencies of acidic, neutral, and basic amino acids. This may be explained by different reaction mechanisms of the chiral inversion and hydrolysis of thalidomide. Chiral inversion is deduced to occur by electrophilic substitution involving specific and general base catalysis, whereas hydrolysis is thought to occur by nucleophilic substitution involving specific and general base as well as nucleophilic catalysis. As nucleophilic attack is sensitive to steric properties of the catalyst, steric hindrance might be the reason albumin is not able to catalyze hydrolysis. 1H NMR experiments revealed that the three teratogenic metabolites of thalidomide, in sharp contrast to the drug itself, had complete chiral stability. This leads to the speculation that, were some enantioselectivity to exist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stable teratogenic metabolites.

Algorithms↗
PubMed1998

Mechanisms of liposomes/water partitioning of (p-methylbenzyl)alkylamines.

PURPOSE: The objective of this study was to compare and interpret the variations in lipophilicity of homologous (p-methylbenzyl)alkylamines (MBAAs) in isotropic (octanol/water) and anisotropic (zwitterionic liposomes/water) system. METHODS: Two experimental approaches were used, namely the pH-metric method to measure lipophilicity parameters in octanol/water and liposomes/water systems, and changes in NMR relaxation rates to validate the former method and to gain additional insights into the mechanisms of liposomes/water partitioning. RESULTS: For long-chain homologues (N-butyl to N-heptyl), the octanol/water and liposomes/water systems mostly expressed hydrophobicity. In contrast, the lipophilicity of the shorter homologues (N-methyl to N-propyl) in the two systems expressed various electrostatic and polar interactions. CONCLUSIONS: The study sheds light on the molecular interactions between zwitterionic liposomes and amphiphilic solutes in neutral and cationic form.

1-Octanol↗
PubMed1998

Evidence for the existence of [3H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore.

1. Trimetazidine is an anti-ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]-trimetazidine on a purified preparation of rat liver mitochondria. 2. [3H]-trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 microM. The total concentration of binding sites is 113 pmol mg(-1) protein. Trimetazidine binding sites are differently distributed. The high-affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low-affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg(-1) protein. 3. Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]-trimetazidine binding sites are different from previously described mitochondrial sites. 4. The possible involvement of [3H]-trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage-dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert-butylhydroperoxide (t-BH). This effect was concentration-dependent with an IC50 value of 200 microM. 5. Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]-trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes. 6. A strong correlation between swelling inhibition potency and low-affinity [3H]-trimetazidine binding sites was observed: r=0.907 (n=24; P<0.001). 7. These data suggest that mitochondrial sites labelled with [3H]-trimetazidine may be involved in the MTP inhibiton.

Animals↗
PubMed1998

Molecular modeling of hen egg lysozyme HEL[52-61] peptide binding to I-Ak MHC class II molecule.

A bound conformation of the antigenic decapeptide hen egg lysozyme HEL[52-61] associated to the mouse MHC class II (MHC II) I-Ak was modeled by homology with the three-dimensional structure of hemagglutinin HA[306-318]-HLA-DR1 complex. HEL peptide Tyr53 could not be aligned with the HA peptide Tyr308 because this resulted in a buried Tyr53 side chain within the I-Ak peptide-binding groove and this conflicted with this side chain being recognized by T cells. Therefore, Asp52 of HEL was fixed as the P1 anchor and aligned on Tyr308 of HA. After molecular dynamics, the modeled complex was stable even in the absence of any constraint. The peptide backbone adopted a polyproline II-like conformation with canonical hydrogen bonding between the peptide backbone and MHC II molecule. Asp52, IIe55, Gin57 and Ser60 were predicted to be deeply buried into P1, P4, P6 and P9 MHC II pockets, and Tyr53, Leu56, Asn59 and Arg61 as TCR contacting residues. The modeling of 15 complexes associating I-Ak with peptides derived from HEL[52-61] by single amino acid substitution proved stable with conserved hydrogen bonds and side chain orientation compatible with their recognition by two T cell hybridomas. Moreover, comparison with the recently solved crystal structure of the related HEL[50-62]-I-Ak complex revealed striking similarities.

Amino Acid Sequence↗
PubMed1998

Ligand specificity of the genetic variants of human alpha1-acid glycoprotein: generation of a three-dimensional quantitative structure-activity relationship model for drug binding to the A variant.

Human alpha1-acid glycoprotein (AAG) is a mixture of at least two genetic variants: the A variant and the F1 and/or S variant or variants, which are encoded by two different genes. In a continuation of previous studies indicating specific drug transport roles for each AAG variant according to its separate genetic origin, this work was designed to (1) determine the affinities of the two main gene products of AAG (i.e., the A variant and a mixture of the F1 and S variants) for 35 chemically diverse drugs and (2) to obtain meaningful 3D-QSARs for each binding site. Affinities were obtained by displacement experiments, leading to qualitative indications about binding site characteristics. In particular, drugs binding selectively to the A variant displayed some common structural features, but this was not seen for the F1*S variants. Three-dimensional QSAR analyses using the CoMFA method yielded a steric model for binding to the A variant, from which a simplified haptophoric model was derived. In contrast, no statistically sound model was found for the F1*S variants, possibly due (among other reasons) to an insufficient number of high affinity ligands in the set.

Alleles↗
PubMed1997

H3-receptor antagonists: synthesis and structure-activity relationships of para- and meta-substituted 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazoles.

We report the synthesis, octanol/water partition coefficient (log P), dissociation constants (pKa), H3-receptor affinity (pKi in rat brain membranes, [3H]-N alpha-methylhistamine), and H3-antagonist potency (pA2 in guinea ileum, (R)-alpha-methylhistamine) of novel H3-receptor antagonists obtained by introducing a para or meta substituent on the phenyl ring of the lead compound 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazole (3a). The substituents were chosen to obtain broad and uncorrelated variation in their lipophilic, electronic, and steric properties. The log P values of the neutral species cover almost 3 orders of magnitude (from 1.40 to 4.11). The pKa,2 values (protonation of the 2-thioimidazole fragment) vary from 3.13 to 4.34, indicating that this fragment, which incorporates the so-called polar group common to many H3-receptor antagonists, is neutral at physiological pH. The compounds had pKi values in a range too narrow (from 7.28 to 8.03) to derive QSAR equations. In one case (3g), a biphasic displacement curve was observed (pKi,1 = 8.53; pKi,2 = 6.90). The pA2 values ranged 2 orders of magnitude (from 6.83 to 8.87) and yielded a QSAR model (PLS) indicating that antagonist potency depends parabolically on lipophilicity and is decreased by bulky para substituents. The compounds of this series, therefore, maintain a fair-to-good affinity for rat brain H3-receptor and a fair-to-good H3-antagonist potency on guinea pig ileum, although varying markedly in their lipophilicity. The series thus appears as a good candidate for pharmacokinetic optimization leading to brain-penetrating H3-receptor antagonists.

Animals↗