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Biomedical subjects

M Langlois

Publications and source records attributed to M Langlois.

At least 37 records · Page 2Linked to original sources
PubMed1999

Haptoglobin polymorphism and peripheral arterial occlusive disease.

Haptoglobin (Hp) 2-2 phenotype is a genetic risk factor in coronary atherosclerosis. In this study, haptoglobin phenotypes were determined in 141 patients with peripheral arterial occlusive disease (PAOD) and compared to a reference population (n = 1000). The relative Hp1 allele frequency was decreased among PAOD patients (0.294 vs. 0.403 for the reference population, P < 0.01) due to an overrepresentation of the Hp 2-2 phenotype (50%, odds ratio 1.82 (95% C.I. 1.28-2.60), P < 0.001). This finding was even more pronounced in non-diabetic and in non-smoking PAOD patients (Hp1 allele frequencies: 0.265 and 0.228, respectively). Serum lipids, inflammatory parameters, and blood pressure levels were comparable among the Hp phenotypes, but serum levels of the antioxidant vitamin C were lower in Hp 2-2 patients than in patients with another phenotype (P < 0.05). In PAOD patients with severe atherosclerotic lesions, maximal walking distance of patients carrying a Hp 2-2 phenotype (225-525 m) exceeded that of other Hp phenotypes (50-242 m) (interquartile ranges) (P < 0.05). The findings demonstrate that, despite an increased risk for developing PAOD, the Hp 2-2 phenotype is associated with a longer maximal walking distance which might be attributed to the earlier reported in vitro angiogenic properties of the Hp 2-2 molecule.

Aged↗
PubMed1999

Synthesis of beta-substituted naphth-1-yl ethylamido derivatives as new melatoninergic agonists.

Naphthalene melatoninergic ligands with alkyl groups (Me, Et, Pr, Bz) in the beta position of the ethylamido chain were synthesised. The affinity of the compounds for chicken brain melatonin receptors was evaluated using 2-[125I]-iodomelatonin as the radioligand. An increase in the affinity was observed with the beta-methyl derivatives and the greatest increase was seen with the (-) enantiomers. The introduction of a 2- or 7-MeO group on the naphthalene ring and the lengthening (Et, Pr) of the alkylamido chain gave potent compounds such as (-)1h (Ki = 24 pM). The functional activity of these compounds was evaluated by the aggregation of melanophores in Xenopus laevis tadpoles. The potency to produce lightening of the skin of Xenopus laevis was related to the affinities values of the molecules at melatonin chicken brain receptors. The most potent ligands were found to be full agonists and compound 1h was 25 fold more potent than melatonin in this bioassay.

Animals↗
PubMed1999

Intestinal prokinesia by two esters of 4-amino-5-chloro-2- methoxybenzoic acid: involvement of 5-hydroxytryptamine-4 receptors and dissociation from cardiac effects in vivo.

In five fasting, conscious dogs, we compared the prokinetic action of two selective 5-hydroxytryptamine-4 (5-HT4) receptor agonists with low affinity for 5-HT3 receptors ML10302 (2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate) and SR59768 (2-[(3S)-3-hydroxypiperidino]ethyl 4-amino-5-chloro-2-methoxybenzoate) in the duodenum and jejunum, using cisapride as a reference compound. Heart rate and rate-corrected QT (QTc) also were monitored to assess whether or not the cardiac effects of cisapride are shared by other 5-HT4 receptor agonists. Both ML10302 and SR59768 dose-dependently stimulated spike activity in the duodenum with similar potencies (dose range, 3-300 nmol/kg i.v.; ED50 values: 24 and 23 nmol/kg i.v., respectively), mimicking the effect of cisapride (30-3000 nmol/kg i.v.). The maximal effect was achieved with the dose of 100 nmol/kg i.v. for both compounds. Similar findings were obtained in the jejunum. Atropine and GR125487 (1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate, selective 5-HT4 receptor antagonist), at doses having no effect per se, antagonized intestinal prokinesia by maximal doses of ML10302 and SR59768. Neither ML10302 nor SR59768 had any effect on heart rate or QTc at any of the doses tested, whereas cisapride, at the highest dose (3000 nmol/kg), induced tachycardia and lengthened the QTC (p <.01). In conclusion, ML10302 and SR59768 share with cisapride a similar prokinetic action in the canine duodenum and jejunum in vivo. This effect is mediated by pathways involving activation of 5-HT4 and muscarinic receptors. Unlike cisapride, which induces tachycardia and prolongs the QTc by a mechanism probably unrelated to 5-HT4 receptor activation, ML10302 and SR59768 are devoid of cardiac effects in this model.

Aminobenzoates↗
PubMed1998

Synthesis of benzocycloalkane derivatives as new conformationally restricted ligands for melatonin receptors.

Benzocycloalkane derivatives 1-4 were synthesized as new conformationally restricted melatoninergic ligands. They were prepared by the reaction of the ketones 5 with diethylcyanophosphonate and the reduction of the corresponding cyano compounds or by the Wittig reaction and Curtius degradation to obtain the amines 8. The 1-Cyanobenzocyclobutane derivative was obtained by the benzyne cyclisation reaction. The amines 8 were acylated with acetyl, propionyl or butyryl groups. The affinity of the compounds for chicken brain melatonin receptors was evaluated using 2-[125I]-iodomelatonin as the radioligand. The indanyl (2b,c), tetralin (3a-c) and benzocycloheptane (4c) derivatives were potent compounds with nanomolar affinity and an important enantioselectivity of the receptor was observed with the (+) enantiomers 2b and 3b.

Alkanes↗
PubMed1998

Synergistic neurochemical and behavioral effects of fluoxetine and 5-HT1A receptor antagonists.

We studied the ability of WAY 100635 [N-[4-(2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide], 0.5 mg/kg, i.v. and (-)-5-Me-8-OH-DPAT [(-)-5-methyl-8-hydroxy-2-(di-n-propylamino)tetralin], 3 mg/kg, i.v. two selective 5-HT1A receptor antagonists, to potentiate: (1) the enhancement of extracellular 5-HT levels ([5-HT(ext)]) induced by a single administration of 5 mg/kg i.p. fluoxetine using in vivo microdialysis in the ventral hippocampus of conscious rats, (2) the decrease in food intake induced by this antidepressant drug in food-deprived rats. The effects of fluoxetine were significantly potentiated, by 30-40%, by WAY 100635 as well as by (-)-5-Me-8-OH-DPAT in the two sets of experiments. Thus, fluoxetine increased [5-HT(ext)] in serotonergic nerve terminal areas and consequently, induced hypophagia, both effects being limited by indirect activation of somatodendritic 5-HT1A autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Effects of WAY 100635 and (-)-5-Me-8-OH-DPAT, a novel 5-HT1A receptor antagonist, on 8-OH-DPAT responses.

The neurochemical profile at both post and presynaptic 5-HT1A receptors of a novel 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) analog, 5-methyl-8-hydroxy-2-(di-n-propylamino)tetralin ¿(+/-)-5-Me-8-OH-DPAT¿ and its stereoisomers was determined and compared to that of the highly selective 5-HT1A receptor antagonist, N-[4-(2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide (WAY 100635). We evaluated their effects on 8-OH-DPAT-induced decrease in cAMP production, on 8-OH-DPAT-induced decrease in rat ventral hippocampal extracellular 5-hydroxytryptamine (5-HText) levels and in body temperature in mice. Both (+/-)- and (-)-5-Me-8-OH-DPAT blocked the 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP production. Moreover, while having no significant effect when injected alone, (+/-)-, (-)-5-Me-8-OH-DPAT and WAY 100635 antagonized the 8-OH-DPAT-induced decrease in 5-HText in rats and hypothermia in mice. By contrast, the (+) isomer inhibited the cAMP synthesis and did not modify the 8-OH-DPAT response on 5-HText in ventral hippocampus. These data suggest that (+/-)-5-Me-8-OH-DPAT acts selectively, its activity residing in the (-) enantiomer, this latter compound acting similarly to WAY 100635 as a full, selective and silent 5-HT1A antagonist.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The 5-HT4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT4(c) receptor.

Transient expression in COS-7 cells of the recombinant human 5-hydroxytryptamine (5-HT) h5-HT4(c) receptor isoform led to constitutive activity of the receptor. The 5-HT4 receptor antagonist 2-(cis-3,5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate (ML10375) at 1 microM completely abolished the 5-HT (1 microM)-mediated increase in adenylyl cyclase activity in COS-7 cells expressing the h5-HT4(c) receptor. Moreover, ML10375 also reduced basal cAMP levels in cells over-expressing the receptor, even in the absence of agonist. The inhibitory effect of ML10375 on basal adenylyl cyclase activity was not modified by pre-treatment of the cells with pertussis toxin, indicating that ML10375 acts through inactivation of spontaneously active h5-HT4(c) receptors rather than through a Gi/Go regulatory pathway. We conclude that ML10375 acts as an inverse agonist on the h5-HT4(c) receptor.

Adenylate Cyclase Toxin↗
PubMed1998

Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus.

We report here the molecular cloning of three new splice variants of the human serotonin 5-hydroxytryptamine4 (h5-HT4) receptor, which we named h5-HT4(b), h5-HT4(c), and h5-HT4(d). The sequence following the splicing site at Leu358 in the C-terminal tail of h5-HT4(b) displays a 74% protein identity with the same region in the long form of the rat 5-HT4 receptor (r5-HT4L) but is shorter by 18 amino acids compared to its rat counterpart. The splice variants h5-HT4(c) and h5-HT4(d) are the first of their kind to be described in any animal species. The C terminus of h5-HT4(c) displays a high number of putative phosphorylation sites. The h5-HT4(d) isoform corresponds to an ultrashort form of the receptor, with a truncation two amino acids after the splicing site. Tissue distribution studies revealed some degree of specificity in the pattern of expression of the different isoforms within the human body. The four splice variants transiently expressed in COS-7 cells displayed an identical 5-HT4 pharmacological profile and showed a similar ability to stimulate adenylyl cyclase activity in the presence of 5-HT. The stimulatory pattern of cyclic AMP formation in response to the 5-HT4 agonist renzapride was found to be significantly different between h5-HT4(a) and the other h5-HT4 isoforms, indicating that the splice variants may differ in the way they trigger the signal transduction cascade following receptor activation.

Alternative Splicing↗
PubMed1998

Effect of haptoglobin phenotypes on growth of Streptococcus pyogenes.

The haptoglobin (Hp) 2-1 and 2-2 phenotypes have been shown to agglutinate Streptococcus pyogenes carrying the membrane antigen T4. In this study, the growth rate of two strains of Streptococcus pyogenes (T1 and T4) in human serum was compared among haptoglobin phenotypes in vitro. During incubation for 16 hours in serum of different haptoglobin types, only Hp 2-1 and Hp 2-2 sera showed an inhibitory effect on growth, Hp 2-2 being 1.85 times more potent than Hp 2-1. Growth of Streptococcus pyogenes T4 negatively correlated with the serum concentration of Hp 2-1 (r = -0.908) and Hp 2-2 (r = -0.953). Haptoglobin-depleted serum had no inhibitory effect on bacterial growth. Addition of haemoglobin and ferric citrate to the serum accelerated the growth of Streptococcus pyogenes T4 (P <0.05) but not in Hp 2-2 serum. Haptoglobin types 2-1 and 2-2 can be regarded as inhibitors of Streptococcus pyogenes growth in vitro. These data point towards a potential protective role of Hp 2-2 in Streptococcus pyogenes infection in vivo, independently of iron uptake.

Antigens, Bacterial↗
PubMed1997

Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.

5-Hydroxytryptamine (5-HT) has been shown to exert positive inotropic, chronotropic, and lusitropic effects and to stimulate the L-type calcium channel current (I(Ca)) in human atrial tissue through activation of the pharmacologically defined 5-HT4 receptor subtype. However, the molecular nature of the receptor(s) involved in these effects is still unknown. In the present study, we report the molecular nature of a 5-HT4 receptor cloned from human atrium, h5-HT4A. Sequence analysis reveals that h5-HT4A displays a 93% protein identity with the short form of the 5-HT4 receptor recently isolated from rat brain. h5-HT4A mRNA is expressed in human atrium but not ventricle, and is also found in brain and GI tract. h5-HT4A transiently expressed in COS-7 cells displays a classical 5-HT4 pharmacological profile. However, affinities of the h5-HT4A receptor for agonists such as ML10302, BIMU1, renzapride or zacopride were 4-10-fold lower than the ones found in brain. Moreover, the stimulatory patterns of cAMP formation by h5-HT4A in response to the 5-HT4 agonists ML10302 and renzapride were very similar to the patterns of stimulation of I(Ca) obtained in response to these compounds in human atrial myocytes. We conclude that h5-HT4A likely mediates the effects of 5-HT in human atrium and may differ from 5-HT4 receptor isoforms present in the brain and GI tract.

Adolescent↗
PubMed1997

Haptoglobin polymorphism, a genetic risk factor in coronary artery bypass surgery.

Haptoglobin (Hp) 2-2 type has been associated with accumulation of atherosclerotic lesions in essential hypertension. The aim of this study was to investigate the relationship between Hp type and the extension of coronary lesions in 765 male patients who underwent coronary artery bypass grafting (CABG). In this group, relative Hp1 (0.418) and Hp2 (0.582) allele frequencies were comparable with those of the reference population. Candidate CABG patients with a Hp 2-2 type were overrepresented in the younger (< 45 years) age group (P < 0.05). Hp 2-2 patients needed more bypass grafts than Hp 1-1 patients (relative risk 1.92 95% C.I. 1.24-2.96). The Hp 2-2 type was overrepresented among victims of a previous acute myocardial infarction (P < 0.05) and among patients with a lower (< 45 years) age at infarction (P < 0.05). In patients who already underwent a previous CABG graft survival time was shortest in Hp 2-2 type (P < 0.05). Patients with a Hp 2-2 type more likely develop atherosclerotic lesions despite comparable serum lipid concentrations.

Adult↗
PubMed1997

Arylcarbamate derivatives of 1-piperidineethanol as potent ligands for 5-HT4 receptors.

A series of carbamate derivatives (7) of 2-(1-piperidinyl)ethyl 4-amino-5-chloro-2-methoxybenzoates, which have been described as potent agonists and antagonists of 5-HT4 receptors, were synthesized. They were evaluated using radioligand binding assays with [3H]GR 113808, a 5-HT4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig. In contrast to the previously described ester derivatives, a drop in the affinity for 5-HT4 receptors was observed and the compounds were inactive as agonists in the guinea pig ileum preparation. Unexpectedly, the ortho-substituted carbamates 8b,c (R' = H, RO = MeO or EtO, R" = H) had nanomolar affinity for 5-HT4 receptors (Ki = 8.9 +/- 0.5 and 2.6 +/- 0.4 nM, respectively). As reported previously, the cis- or trans-3,5-dimethyl substitution of piperidine (8n,o) was particularly favorable (Ki = 1.1 +/- 0.6 nM for both isomers). 8c is an antagonist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1).

Animals↗
PubMed1997

Three-dimensional quantitative structure-activity relationship of melatonin receptor ligands: a comparative molecular field analysis study.

A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized previously and reported to be active at chicken brain melatonin receptors were divided into a training set of 48 molecules and a test set of 9 molecules. As most of these compounds have a highly flexible ethylamido side chain, the alignments were based on the most sterically constrained molecule which contains a tricyclic phenalene structure. This tricyclic compound can adopt an axial and an equatorial conformation. Two different molecular superpositions representing possible positioning within the receptor site have been suggested previously. CoMFA was tentatively used to discriminate between alternate hypothetical biologically active conformation and between possible positionings. The best 3D quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.798, 0.967, and 0.76, respectively, along with an average absolute error of prediction of 0.25 log units. These results suggest that the active conformation of the most flexible molecules including melatonin is in a folded form if we consider the spatial position of the ethylamido side chain relative to the aromatic ring.

Animals↗
PubMed1997

New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and antagonists for 5-HT4 receptors.

A number of benzoates derived from 4-amino-5-chloro-2-methoxybenzoic acid and substituted 1-piperidineethanol were synthesized and found to be potent 5-HT4 receptor agonists in the electrically-stimulated myenteric plexus and longitudinal muscle of the guinea pig ileum and the rat esophagus muscle. Monosubstitution of the piperidine ring with Me, OH, NH-Ac, or CONH2 groups gave compounds equipotent to 7a (ML 10302), a 5-HT4 receptor agonist previously reported to have nanomolar affinity. 7a,k were as potent as serotonin (5-HT) but had maximal responses which were only 60-80% of that of 5-HT, suggesting a partial agonist profile for these compounds. Binding assays were performed with [3H]GR 113808 in the rat striatum, and several of these compounds were found to have nanomolar affinity for 5-HT4 receptors (7a, Ki = 1.07 +/- 0.5 nM; 7k, Ki = 1.0 +/- 0.3 nM). The introduction of two methyl groups on the piperidine ring brought about a dramatic change in the pharmacological profile of 2-[(cis- and trans-3,5-dimethylpiperidinyl)ethyl]-4-amino-5-chloro-2- methoxybenzoate, 7g,h. 7g (Ki = 0.26 +/- 0.06 nM) inhibited the relaxant action of 5-HT in the rat esophagus muscle with a pA2 value of 8.6. The advantage of the ester function was demonstrated by comparing the activity of several such compounds at 5-HT4 receptors with those of the corresponding amidic derivatives. This difference was less marked when the basic moiety was sterically constrained as in the quinuclidine and tropane moieties. Structural analyses of 7a,g were performed by determining their X-ray crystal structures and by molecular modeling (SYBYL). A relatively limited number of minimum energy conformers was found for both compounds. They were characterized by the cis folded conformation of the ethyl chain and by the orientation of the lone pair of the nitrogen atom pointing out of the molecule as seen in conformationally-constrained benzamides such as zacopride and renzapride. A hypothetical model for the 5-HT4 receptor with two sites for the binding of agonist and antagonist molecules was proposed.

Animals↗
PubMed1997

Rapid direct diagnosis of mumps meningitis by ELISA capture technique.

ELISA capture technique (ELISAc) was carried out using a rabbit hyperimmune serum attached to a solid phase for capturing mumps antigens in cerebrospinal fluid (CSF) in patients with meningitis and/or in supernatants of infected Vero cells. A biotin-labelled rabbit serum prepared from the previous serum was added and the reaction was read by an enzymatic (avidine-peroxidase) reaction by automated reading. The cut-off was calculated in 100 CSFs negative for viruses by conventional diagnosis. The specificity was evaluated in Vero cells infected with 22 CSFs collected from vaccinated children (URABE AM9 attenuated vaccine) who developed meningitis. A guinea pig hyperimmune serum confirmed the specificity. Results in culture correlated with the ELISA capture technique (ELISAc). No cross-reactivity was observed with parainfluenza 1, 2, 3 human reference strains. At least 2.5 ngs of purified mumps proteins were detected corresponding to 10(1.5) infectious particles per ml. ELISAc applied directly to 14 CSFs collected from unvaccinated children with meningitis diagnosed five positive cases, whereas in four cases conventional diagnosis had to be undertaken twice. ELISAc permitted the diagnosis of one additional patient. The test can be carried out in 3 h.

Animals↗