Antimalarial activity of methylpiperazinyl-substituted benzophenone-based farnesyltransferase inhibitors.
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Animals↗
Biomedical subjects
R Ortmann
Publications and source records attributed to R Ortmann.
Novel lead structures for antimalarial farnesyltransferase inhibitors.
Through the combination of nitrophenylfurylacryloyl moiety which has been designed to occupy an aryl binding site of farnesyltransferase with several AA(X)-peptidomimetic substructures some novel farnesyltransferase inhibitors were obtained. Evaluation of their antimalarial activity and some initial modifications yielded a 4-benzophenone- and a sulfonamid-based novel lead for antimalarial farnesyltransferase inhibitors.
Alkyl and Aryl Transferases↗
2-(aminoacylamino)benzophenones: farnesyltransferase inhibition and antimalarial activity.
The use of amino acids as acyl substitutents at the 2-amino group of our benzophenone core structure yielded compounds with mainly good to moderate farnesyltransferase inhibitory and moderate antimalarial activity. However, these farnesyltransferase inhibitors display some degree of selectivity towards malarial parasites since there was no cytotoxic activity observed at 70-80 microM.
Amino Acids↗
2-(Arylpropionylamino)- and 2-(arylacryloylamino)benzophenones: farnesyltransferase inhibition and antimalarial activity.
Structural variation of the 2-acylamino moiety of some benzophenone farnesyltransferase inhibitors led to the para-trifluoromethylphenylpropionyl derivative with relatively low farnesyltransferase inhibition but considerable antimalarial activity and no cytotoxicity.
Alkyl and Aryl Transferases↗
Inhibitors of farnesyltransferase: 5-arylacryloylaminobenzophenones show antimalarial activity.
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Alkyl and Aryl Transferases↗
Structure-activity relationships of novel anti-malarial agents part 8. Effect of different central aryls in biarylacryloylaminobenzophenones on antimalarial activity.
Replacement of the 2,5-disubstituted furyl residue present in the known antimalarial agents 8 by other aryl residues resulted in a more or less reduced antimalarial activity in most cases. The only exemption was the 2,4-thienylene compound 11a displaying activity with an IC50 value of 120 nM. In conclusion, the 2,5-furylene compound 8e remains to represent the most active antimalarial agent in this series of farnesyltransferase inhibitors.
Alkyl and Aryl Transferases↗
A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis.
B10.Q mice are normally susceptible to the induction of collagen-induced arthritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely resistant to disease induction when immunized with collagen in CFA. B10.Q/J mice have a global defect in the generation of Th1 responses, and Ag-specific T cells derived from this strain failed to produce IFN-gamma. Because T cells from these mice could produce normal amounts of IFN-gamma when activated by IL-12/IL-18-independent stimuli, the defect appeared to be a failure to respond to IL-12. This defect extended to NK cells, which also failed to produce IFN-gamma when stimulated by IL-12. The capacity of NK cells, but not activated T cells, to produce IFN-gamma in response to IL-12 could be partially restored by IL-18. The expression of the IL-12R beta1- and beta2-chains on T cells and NK cells from B10.Q/J mice was normal. However, activated T cells from B10.Q/J mice did not signal normally through the IL-12R and manifested a defect in their capacity to phosphorylate Stat4. This defect was partial in that it could be overcome by increasing both the concentration of IL-12 and the incubation times in the Stat4 phosphorylation assays. Because Stat4 function is apparently intact in B10.Q/J mice, the defect in IL-12 signaling can be localized between the IL-12R complex and Stat4. This subtle abnormality in IL-12 responsiveness results in a profound defect in the generation of Th1 cells and the development of autoimmune disease.
Animals↗
A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment.
This study documents a defect in IL-12-dependent IFN-gamma responses in a substrain (B10.Q-H2-(q)/SgJ) of B10.Q mice that manifests as an acute susceptibility to infection by the intracellular protozoan pathogen, Toxoplasma gondii. Despite robust systemic production of IL-12, infected B10.Q/J animals fail to mount an early IFN-gamma response after parasite inoculation. Genetic experiments revealed that the host resistance and IFN-gamma production defects are determined by a single autosomal recessive locus distinct from the Stat4 gene. Nonetheless, a delayed IL-12-mediated IFN-gamma response emerges in later stages of acute infection but is unable to prevent host mortality. IL-18 administration restores, in an IL-12-dependent manner, the early IFN-gamma response and host resistance of B10.Q/J animals. These in vivo studies indicate that the partially impaired IL-12 responsiveness in B10.Q/J mice can result in defective host resistance and demonstrate a therapeutic function for IL-18 in reversing a genetically based immunodeficiency in IL-12-dependent IFN-gamma production.
Acute Disease↗
Position-independent expression of a human nerve growth factor-luciferase reporter gene cloned on a yeast artificial chromosome vector.
Two yeast artificial chromosomes containing the entire human nerve growth factor gene were isolated and mapped. By homologous recombination a luciferase gene was precisely engineered into the coding portion of the NGF gene and a neomycin selection marker was placed adjacent to one of the YAC telomeres. Expression of the YAC-based NGF reporter gene and a plasmid-based NGF reporter gene were compared with the regulation of endogenous mouse NGF protein in mouse L929 fibroblasts. In contrast to the plasmid-based reporter gene, expression and regulation of the YAC-based reporter gene was independent of the site of integration of the transgene. Basic fibroblast growth factor and okadaic acid stimulated expression of the YAC transgene, whereas transforming growth factor-beta and dexamethasone inhibited it. Although cyclic AMP strongly stimulated production of the endogenous mouse NGF, no effect was seen on the human NGF reporter genes. Downregulation of the secretion of endogenous mouse NGF already occurred at an EC50 of 1-2 nM dexamethasone, but downregulation of the expression of NGF reporter genes occurred only at EC50 of 10 nM. This higher concentration was also required for upregulation of luciferase genes driven by the dexamethasone-inducible promoter of the mouse mammary tumor virus in L929 fibroblasts.
Animals↗
Is there a long-lasting effect of a short-term nerve growth factor application on axotomized rat septohippocampal neurons?
Loss of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum (MS) following fimbria transection can be prevented by nerve growth factor (NGF) application. Here we have studied the long-term effects of a short-term NGF treatment starting immediately after lesion and lasting for the first 3 weeks. We demonstrate that this NGF treatment rescues many ChAT neurons after short survival time (3 weeks) but does not have a long-lasting (6 months) effect on both ChAT- and parvalbumin-immunopositive (GABAergic) MS neurons.
Animals↗
Astrocyte-derived TGF-beta 2 and NGF differentially regulate neural recognition molecule expression by cultured astrocytes.
Because of the importance of neural recognition molecules expressed by glial cells to mediate interactions with neurons, growth factors and cytokines known to be functional during morphogenesis and in diseases of the nervous system were studied for their effects on recognition molecule expression by cultured immature and mature astrocytes from several brain regions. In cultures of immature astrocytes, transforming growth factors-beta 1 (TGF-beta 1) and -beta 2 (TGF-beta 2) and nerve growth factor (NGF) increased expression of the neural adhesion molecule L1, leading to a glia-mediated L1-specific increase in neurite outgrowth of dorsal root ganglion neurons on the astrocyte substrate. L1 expression induced by TGF-beta was inhibited by addition of antibodies to NGF, suggesting that TGF-beta influences L1 expression by modulating production of NGF by astrocytes. TGF-beta 1 and -beta 2 decreased expression of N-CAM by immature astrocytes. Since N-CAM expression was not affected by NGF and antibodies to NGF did not abolish the TGF-beta-induced decrease in N-CAM expression, NGF did not appear to be the mediator for regulating expression of N-CAM. Expression of the adhesion molecule on glia (AMOG) was not affected by any factor. NGF and TGF-beta 2 in latent form, but not TGF-beta 1 were found in the culture supernatants. Addition of interferon-gamma (IFN-gamma), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), platelet-derived growth factor (PDGF), or basic fibroblast growth factor (bFGF) to the cultures did not change recognition molecule expression. REcognition molecule expression by mature astrocytes was not found to be modified by any of the factors tested. In view of the observation that levels of L1 and N-CAM expression correlated with the presence of TGF-beta 2 and NGF in the culture supernatants of immature astrocytes, an autocrine regulatory mechanism for recognition molecule expression by these cells is suggested to play a crucial role in regulation of neuron-glia interactions.
Adenosine Triphosphatases↗
Induction of glia-derived nexin after lesion of a peripheral nerve.
Glia-derived nexin (GDN), also known as protease nexin I, is a serine protease inhibitor of deduced relative molecular mass 41,700, identified in conditioned media of glioma cells by its neurite-promoting activity. GDN can promote neurite outgrowth in vitro from neuroblastoma cells, sympathetic neurons and hippocampal neurons (L. Farmer et al., manuscript in preparation). In vivo, GDN is constitutively expressed in all parts of the olfactory system, where axonal regeneration and neurogenesis occur continuously throughout life. This observation indicates that GDN could be important for axonal regeneration in vivo. To investigate this possibility, we have taken advantage of the fact that damage to nerves in the peripheral nervous system leads to their regeneration, whereas in the central nervous system no such regeneration can occur. Here we report that after lesion of the rat sciatic nerve there is a large transient increase in the amount of GDN messenger RNA and of released GDN. The cells showing GDN immunoreactivity are mainly localized distal to the lesion site. These results further support the suggestion that GDN is important for axonal regeneration in vivo, and indicate that protease inhibitors could have a role in Wallerian degeneration and peripheral nerve regeneration.
Amyloid beta-Protein Precursor↗
[The sensory cells of the fetal vomeronasal organ in the human. A contribution to the variability of their differentiation and rudimentary development].
Serial cranial sections of seven human fetuses between 11 and 18 weeks were studied using Palmgren's silver impregnation technique. The vomeronasal organ revealed receptor cells in four cases. This is the first demonstration of functional elements in the vomeronasal organ in man. They may also be present in old-world monkeys. It is evident that the human vomeronasal organ is frequently present in man, but differentiation of the organ and its individual constituents shows considerable variation.
Cell Differentiation↗
Cholinomimetics induce theta rhythm and reduce hippocampal pyramidal cell excitability.
The actions of cholinomimetics and of physostigmine were tested on two parameters reflecting hippocampal activity, namely theta activity and pyramidal cell excitability. In rats pretreated with methylscopolamine and anaesthetized with urethane i.v. administration of the cholinomimetics oxotremorine and arecoline and the cholinesterase blocker physostigmine evoked theta wave activity in the hippocampus, which was blocked by scopolamine. Spectral analysis demonstrated that the frequency of the theta waves induced was dose-related, ranging from about 3 Hz to between 5 and 6 Hz. theta Activity could not be induced by arecoline in animals with large septal lesions. Pyramidal cell excitability is known to be increased by endogenous acetylcholine released from cholinergic fibres. In the present study, however, i.v. injections of oxotremorine, arecoline and physostigmine in doses that induce theta activity diminished the excitability of CA1 pyramidal cells in a dose-dependent manner, as judged by the reduction in the amplitude of the population spike and the dendritic epsp. These depressant effects were attenuated by scopolamine but not by methylscopolamine. The depressant effect of arecoline was attenuated in rats with extensive lesions in the medial septal area. The present findings demonstrate that exogenously administered cholinomimetics only partly mimic the action of endogenous acetylcholine in the hippocampus. The central sites of action of exogenously administered cholinomimetics for mediation of theta activity and alteration of pyramidal cell excitability remain to be elucidated.
Acetylcholinesterase↗
Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats.
Long Evans rats were trained to discriminate 0.2 mg/kg IP (+/-)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED50 of (+/-)-rolipram was 0.06 mg/kg IP. Generalization tests with (-)- and (+)-rolipram showed that the (-)-isomer was 8 times more active than (+)-rolipram with an ED50 of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (+/-)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (-)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (+/-)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (+/-)-rolipram in rats remains to be elucidated.
Animals↗
Behavioral effects and general pharmacology of 4-(5-chloro-benzofuranyl-2)-1-methylpiperidine HC1, an antidepressant inhibiting both monoamine oxidase A and 5-hydroxytryptamine uptake.
In psychopharmacological tests in rats and mice, 4-(5-chloro-benzofuranyl-2)-1-methylpiperidine HC1 (CGP 4718 A) was found to exert behavioral effects typical of both monoamine oxidase (MAO)-A and 5-hydroxytryptamine (5-HT) uptake inhibitors (reserpine antagonism, L-5-HTP potentiation, antiaggressive activity in isolated mice). The potential antidepressant activity of the drug was indicated in rats by antagonism of reserpine and its effect in the social-conflict test. CGP 4718 A did not impair motor coordination and had no influence on locomotor activity up to high doses in mice and rats. In monkeys, it increased directed individual activities, including sex-related behaviors and diminished locomotor activity and passivity. Electroencephalographic studies in cats revealed a significant decrease in paradoxical sleep after treatment with CGP 4718 A. In isolated organs, no significant antagonism of norepinephrine, 5-HT, acetylcholine or histamine was found. Cardiovascular studies in cats showed only transient effects on blood pressure and no effect on heart rate. In conscious dogs no cardiovascular effects were found. No potentiation of the pressor effect of tyramine in rats was detectable after repeated doses of up to 300 mg/kg p.o. A weak cardiodepressant effect was seen in isolated guinea pig atria. In conclusion, in animal experiments CGP 4718 A combines an interesting spectrum of antidepressant, activating and antiaggressive properties with a lack of cardiovascular and tyramine-potentiating effects.
Animals↗
The conditioned place preference paradigm in rats: effect of bupropion.
The effect of bupropion in the conditioned place preference paradigm in rats is described. In doses between 10 and 50 mg/kg i.p. bupropion increased the time rats spent in a shuttle box compartment conditioned to this compound. This effect of bupropion was not blocked by pretreatment of the animals with 0.1 mg/kg i.p. haloperidol or 50 mg/kg i.p. sulpiride. The same doses of the neuroleptics did, however, attenuate locomotor hyperactivity induced by bupropion. Bupropion thus seems to belong to the group of CNS stimulants whose effect in the conditioned place preference paradigm is not blocked by neuroleptics.
Animals↗
Place preference conditioning with methylphenidate and nomifensine.
The role of central catecholaminergic systems in place preference conditioning produced by methylphenidate and nomifensine was investigated. Several doses of either methylphenidate or nomifensine produced alterations in place preferences, while desipramine (10 mg/kg), a relatively selective noradrenergic uptake inhibitor, was ineffective, Haloperidol (0.15-0.5 mg/kg) did not attenuate place preferences induced with methylphenidate (2.5 and 5.0 mg/kg) or nomifensine (5.0 mg/kg), although conditioning with methylphenidate (5.0 mg/kg) was blocked after injections of a high dose of haloperidol (1.0 mg/kg). Intraventricular injections of 6-hydroxydopamine had no effect on methylphenidate (2.5 mg/kg) induced place preferences. In contrast, pretreatment with haloperidol (0.2 mg/kg) or intraventricular injections of 6-hydroxydopamine attenuated locomotor activity induced by methylphenidate (5.0 mg/kg). These results suggest that methylphenidate and nomifensine produce place preferences via mechanisms that are either qualitatively or quantitatively distinct from their catecholamine-dependent stimulant actions.
Animals↗