Genevieve Baziard-Mouysset

Evidence that nicotine acetylcholine receptors are not the main targets of cotinine toxicity.

The toxicity of nicotine, cotinine and their mixtures was studied in Mus musculus mice as well their effects on growth after repetitive administration to young mice. The affinity constants of the two alkaloids for the nicotinic acetylcholine receptors (nAChRs) of Torpedo and rat brain membranes were determined. The administration of these alkaloids produced distinct symptoms of intoxication. Nicotine was 100-fold more toxic than cotinine and 10-fold more rapid than cotinine at producing respiratory arrest. The affinity of nicotine for both subtypes of nAChRs was > 100-fold higher than that of cotinine. Repetitive administrations of nicotine caused weight loss, whereas that of cotinine caused weight gain (P < 0.01). The administration of the two alkaloids as mixtures to mice caused significantly (P < 0.01) higher mortality than theoretically expected. Furthermore, hexamethonium pretreatment reduced by 2-fold (P < 0.01) the toxicity of nicotine but enhanced by 1.6-fold (P < 0.01) that of cotinine and was without effects on toxicity of mixtures. We suggest that nAChRs are not the main targets of cotinine toxicity.

Microbiological reductions of chromen-4-one derivatives

Abstract From the microbiological reductions of 2-acetyl or 2-benzoylchromen-4-one both enantiomers of the corresponding alcohols were obtained with high enantiomeric excess. The absolute configurations were determined directly by an X-ray structural determination. The results obtained showed that for most of the microorganisms tested, an inversion of the configuration of the alcohol occurred with the change of the substituent (methyl to phenyl group) in position 2, but also with the presence of a bromine atom in position 6 of the aromatic ring, positioned quite far from the prochiral centre.

Synthesis and antimalarial activity of new atovaquone derivatives.

In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC(50) values in the range of 1.25-50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.

Synthesis and pharmacological study of new calcium antagonists, analogues of cinnarizine and flunarizine

Abstract Several phosphonic diethyl esters were synthesized and their calcium antagonistic activity evaluated in vitro. The diethyl phosphonate group was condensed on substituted [diphenylmethyl], [(2-benzofuranyl)phenylmethyl], [(4-(diphenylmethyl-1-piperazinyl) methyl], [4 (4-diphenylmethyl-1-piperazinyl methyl) phenylmethyl], and [4-(3-phenyl-2-propenyl)-1-piperazinyl methyl] groups. Despite the presence of the diethyl phosphonate moiety and the benzhydrylpiperazinyl group, both present in potent calcium antagonist structures, only 1 of the 19 synthesized compounds exhibited a calcium antagonistic profile.

Synthesis and structure-activity relationships of novel 2-amino alkyl chromones and related derivatives as a site-selective ligands

Abstract Starting from a random screening showing that 2-[(4-benzylpiperazinyl)methyl] chromone was a selective and potent sigma ligand, a series of analogues were synthesized. Introduction of a substituent on the chromone moiety, replacement of methy-lenes by carbonyl groups and benzyl by aryl groups decrease the affinity for sigma sites. The result obtained after introduction of various substituents on the aromatic part of the benzyl is strictly depending on the size and on the position of these substituents. Stretching of the carbon chain between the phenyl and the piperazine does not strongly modify the affinity. 2-[4-(4′-methoxy benzyl)-1-piperazinyl methyl] chromone has been tested in behavioral tests that permit to believe that such derivatives could be interesting for the treatment of psychosis.

Antiproliferative effect induced by novel imidazoline S43126 in PC12 cells is mediated by ROS, stress activated MAPKs and caspases

BACKGROUND Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death. METHODS PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy. RESULTS We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126-induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation. CONCLUSION Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes.

SYNTHESIS AND PROTOZOOCIDAL ACTIVITY OF NEW 1,4-NAPHTHOQUINONES

Four naphthoquinones were submitted to the action of diazomethane. The structure of the nine adducts, of which four were original, was determined. The protozoocidal activity of these compounds was evaluated in vitro against Plasmodium falciparum, Leishmania donovani, Trypanosoma brucei and Trichomonas vaginalis. The 2-methoxy-naphthoquinone 3a exhibited some activity and was more potent against these four protozoa than the reference drugs. The 2-methoxynaphthoquinone 4a showed more activity than chloroquine towards Plasmodium falciparum. Introduction In our previous studies on the reactivity of diazomethane towards cyano derivatives, we showed that diazomethane could react with aromatic or heterocyclic compounds, such as chromones, bearing electroattractive groups (1,2,3). In an extension of these studies, we reacted diazomethane with carbonyl compounds similar to benzopyrones: 1,4-naphthoquinone 1, 2-methyl-1,4-naphthoquinone or menadione Z, 2-hydroxy-1,4naphthoquinone or lawsone 3. and 2-hydroxy-3-(E-4-parachlorophenylcyclohexyl)-1,4-naphthoquinone or atovaquone £ (WellvoneTM) used therapeutically. We chose unsubstituted, monoor disubstituted naphthoquinones in attempt to investigate the difference of reactivity towards diazomethane as a function of the level of substitution and the nature of substituents. We determined the antimalarial activity of the resulting adducts against Plasmodium falciparum. In this respect, several 2-hydroxynaphthoquinones have been described with antimalarial activity, and the quinones are known to interfere with coenzyme Q in the respiratory chain of some protozoa (4). We also studied the activity of these compounds towards flagellate protozoa: Trypanosoma brucei and Leishmania donovani in an attempt to enlarge the protozoocidal activity spectrum, as recent studies (5,6,7) have shown that naphthoquinones possess activity towards Trichomonas vaginalis. Results and Discussion Chemistry The naphthoquinones 1, 2, 3 and 4 were stirred during several days with a solution of diazomethane in diethyl ether. The solvent was evaporated and the residue was chromatographed on a silica gel column (70-230 mesh). The structures were determined using spectroscopic methods (NMR H, 1 C, 2D) and by X-ray diffraction. Addition of diazomethane to 1,4-naphthoquinone 1 gave rise to two N-methylated isomers: l a (8) and 1b. which is an original compound. These products were assumed to be formed after oxidation of the intermediate pyrazoline and methylation of the two prototropic forms of pyrazole (Figure 1). The pyrazoline and pyrazole were not isolated. Vol. 5, No. 4, 1999 Synthesis and photozoocidal activity of new 1,4-naphthquinones

Synthesis and calcium antagonistic activity of diethyl styrylbenzylphosphonates

Abstract Twenty-three new phosphonic ester derivatives of stilbene exhibiting structural analogies with fostedil are described. Examination of calcium antagonism showed that this activity could not be increased by introducing electron-withdrawing, electron-releasing or lipophilic substituents. Only compounds containing fluorine at the 2 or 4 positions exhibited similar activity to the model.

Novel I1-Imidazoline Agonist S43126 Augment Insulin Secretion in Min6 Cells

The I1-imidazoline receptor is a novel drug target for hypertension and insulin resistance which are major disorders associated with Type II diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126 on calcium fluxes and insulin secretion from Min6 β-cells. We also examined the effects of S43126 on the induction of IRAS, and phosphorylation of components in the I1-imidazoline signaling pathways, namely ERK and PKB. Min6 β-cells were treated with varying doses of S43126 [10−8M to 10−5M] for various time (5–60mins). S43126 at higher dose [10−5M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca2+ influx mediated by S43126 [10−5M] were decreased following co-treatment with efaroxan (I1-antagonist) and nifedipine (L-type voltage-gated Ca2+-channel blocker) at various times (5–60mins). Furthermore, S43126 at [10−5M] increased Ca2+ oscillation, [Ca2+] and 45Ca2+ uptake in a time and dose-dependent manner. Moreover, Western blot analysis of treated samples showed that S43126 caused an increased protein expression of IRAS as well as phosphorylation of both ERK1/2 and PKB in a concentration-dependent manner. We conclude that S43126 exerts its insulinotropic effect in a glucose dependent manner by a mechanism involving L-type calcium channels and imidazoline I1-receptors.