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S Rault

Publications and source records attributed to S Rault.

16 recordsLinked to original sources
PubMed1998

[11C]S21007, a putative partial agonist for 5-HT3 receptors PET studies. Rat and primate in vivo biological evaluation.

We recently labeled with carbon-11, a high affinity, selective, 5-HT3 receptor (5-HT3R) ligand, S21007, for potential positron emission tomography (PET) applications. To evaluate the in vivo binding properties of [11C]S21007, its brain regional distribution, tissue and plasma pharmacokinetics and plasma metabolisation were characterized. To circumvent the problem of highly discrete brain localization of the 5-HT3R (area postrema, hippocampus), we designed an original approach combining high-resolution imaging techniques (ex vivo phosphor plate autoradiography and MRI-guided coronal PET in the rat and baboon, respectively). After i.v. injection of trace amounts of [11C]S21007 to rats, phosphorimager autoradiography failed to reveal in vivo specific binding to, nor selectivity for 5-HT3R-rich areas. PET studies in the baboon showed consistent results, i.e., there was no selective accumulation of [11C]S21007 in the area postrema or hippocampus, and neither displacement nor presaturation with cold S21007 resulted in significant changes in tissue distribution or kinetics of [11C]S21007.

Animals↗
PubMed1997

Novel and selective partial agonists of 5-HT3 receptors. 2. Synthesis and biological evaluation of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines.

In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure-activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 10(6). Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.

Animals↗
PubMed1997

Chlorofluorocarbon CFCs, potential alternative HCFCs and HFCs, and related chlorinated compounds: mass spectral study, Part II.

In a previous publication, mass spectrometry was applied to the study of several ions formed by dissociative ionization of ethanes, partially substituted with fluorine and chlorine, and to the determination of the fragmentation pattern of each related compound. The aim of the present investigation was to extend this mass spectral study (70 eV and low ionization energy) to a group of closely related analogs, hydrofluorocarbons (HCFCs), HFCs, chlorinated fluorocarbons, and chlorinated hydrocarbons--halogenated methane, ethane, and propane molecules--to make an attempt to predict the relative bond strength and then the behavior--metabolic pathway and tropospheric degradation--of new HCFCs and HFCs.

Chlorofluorocarbons↗
PubMed1997

In vitro effects of Celiptium and MR 14504 on mature rat Leydig cell testosterone production.

Percoll-purified mature rat Leydig cells have been used to evaluate the testicular toxicity of two highly potent intercalating agents (Celiptium and MR 14505). Testosterone secretion in the absence and in the presence of human chorionic gonadotropin (hCG) was measured to assess Leydig cell function. Celiptium and MR 14504 induce time- and dose-related inhibitory effects on the production of testosterone by Leydig cells, both in the presence and in the absence of hCG, whatever the concentration of hCG used. We have observed that MR 14504 is about 5 times more potent as an inhibitor of rat Leydig cell steroidogenesis than Celiptium without inducing any cell toxicity. The present study indicates that the Leydig cell is an additional potential site for the primary toxic effects of these drugs in the adult rat testis.

Animals↗
PubMed1997

Applicability of the free energies of solvation for the prediction of ecotoxicity: study of chlorophenols.

Free energies of solvation of chlorophenols were calculated in two solvents: water and n-hexadecane from the AMSOL program. These free energies of solvation are the sum of two terms: polarization free energies (delta GENP) and cavity, dispersion, solvent structure free energies (G degree CDS). This study shows, in the case of chlorophenols, that a direct relation exists between one of the two components for the calculation of free energy (G degree CDS) in water and n-hexadecane, and the ecotoxicity values for five biological systems. We point out the interest of using these new descriptors in QSAR study.

Chlorophenols↗
PubMed1996

Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization.

The interaction of S 21007 [5-(4-benzyl piperazin-1-yl)4H pyrrolo [1,2-a]thieno[3,2-e]pyrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C]guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane-anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be prevented by pretreatment with the potent 5-HT3 receptor antagonist zacopride. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist-like properties either by triggering a long lasting receptor desensitization or by a partial agonist activity at 5-HT3 receptors in some tissues.

Animals↗
PubMed1996

Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and biological evaluation of piperazinopyrrolothienopyrazines.

A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine derivatives were prepared and evaluated in order to determine the necessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitutions on the piperazine and the thiophene ring of the pyrrolothienopyrazine moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to very high selectivity (up to 10,000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been evaluated on the Von Bezold-Jarisch reflex and were characterized as partial agonists. One of them, 13a, has shown in vivo at very low dose a potent anxiolytic-like activity in the light/dark test.

Animals↗
PubMed1995

Applicability of CoMFA in ecotoxicology: a critical study on chlorophenols.

Comparative molecular field analysis (CoMFA) is used to relate ecotoxicological data with steric and electrostatic fields of chemicals forming an intentionally selected homogeneous set, the chlorophenols, for which reliable data are abundant in literature. Among these data, those concerning 16 different biological systems were selected, leading to predictive CoMFA QSAR in 14 of the cases. This is attested by cross-validation and bootstrapping, which also authorize the prediction of the chlorophenols toxicity values, when they are missing. The quality of obtained CoMFA models and the applicability of the method are discussed. The results are very promising, and they encourage further investigation into CoMFA in ecotoxicology.

Animals↗
PubMed1994

Mass spectral study of chlorofluorocarbons (CFCs) and potential alternatives (HCFCs and HFCs).

Owing to high ozone depletion potential of the chlorofluorocarbons (CFCs), the production of such substances has been regulated worldwide by the Montreal Protocol in 1987. There is an urgent need to find other suitable products to replace them and hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs) are considered to be the most probable candidates as CFC alternatives. The HCFCs and HFCs are more susceptible to decomposition during use than CFCs because they contain hydrogen. Toxicological data on these alternative fluorocarbons are being developed. A systematic investigation of these compounds has been undertaken to establish the fragmentation patterns. Electron impact mass spectra are reported for HCFCs and HFCs. Fragmentation mechanisms are presented and discussed on the basis of variable energy (11 to 30 eV) spectra. At low ionization energy, it is possible to describe an order of fragmentation for each compound. This may lead to the possibility of classifying them according to characteristic behaviors.

Chlorofluorocarbons↗
PubMed1993

Mutagenicity of nitro- and amino-substituted carbazoles in Salmonella typhimurium. I. Monosubstituted derivatives of 9H-carbazole.

Mononitro, monoamino and monoacetamido carbazoles were assayed for mutagenicity in Salmonella typhimurium strains TA1535, TA1538, TA1537, TA1977, TA98 and TA100, with and without the addition of S9 from phenobarbital-induced rat liver. The role of bacterial metabolism of the nitro group was also studied using the additional strains TA98NR and TA98/1,8DNP6. None of the compounds was active in TA1535, while only 2-nitrocarbazole and 3-nitrocarbazole presented a weak mutagenicity towards its pKM101 derivative, TA100. All four nitrocarbazole isomers were mutagenic for TA1538 and TA98, their activities decreasing in the order: 2-nitrocarbazole approximately 3-nitrocarbazole > 1-nitrocarbazole > 4-nitrocarbazole. Direct-acting mutagenicities for TA1537 were lower than for TA1538, but varied in the same order. Nitro reduction was an important step of metabolic activation of nitrocarbazoles, as indicated by the dramatic reduction of activity with TA98NR, as compared to TA98. Results obtained with TA98/1,8DNP6 showed that O-acetyltransferase was only partly required for the expression of mutagenic potency of these compounds. 2-Aminocarbazole was a weak direct-acting mutagen for TA1538 and TA98. Its activity was strongly increased in the presence of S9 mix, while 3-aminocarbazole became active in these conditions. The acetamido derivatives were consistently less mutagenic than their parent amines. These results show that nitrocarbazoles and aminocarbazoles behave as reactive frameshift mutagens, acting mainly through the formation of esterified hydroxylamines. The very low activity of 4-nitrocarbazole might be related to an orientation of the nitro group perpendicular to the aromatic ring.

Amines↗
PubMed1992

Comparative molecular field analysis of CCK-A antagonists using field-fit as an alignment technique. A convenient guide to design new CCK-A ligands.

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate the affinities of several antagonists towards CCK-A receptors with their steric and electrostatic fields. In this publication, we describe, for the first time, a field-fit operation as an alignment technique. These results could serve as a guide for the design of new non-peptide antagonists.

Amino Acid Sequence↗