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See detailNew pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors
Liégeois, Jean-François ULg; Eyrolles, L.; Ellenbroek, B. A. et al

in Journal of Medicinal Chemistry (2002), 45(23), 5136-5149

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol ... [more ▼]

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K-i > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D-4.2 and 5-HT2A receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-metbylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo [3.2.1] octane derivatives (23, 38) involved a slight reduction of the affinity at D-4.2 and 5-HT2A receptors while the affinity at D-2L receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D-4.2 receptors but some of these molecules (24, 25, 41) presented a significant 5-HT2A binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D-4.2 and 5-HT2A affinity (K-i = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties. [less ▲]

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See detailMinimal effects of JL 13, a pyridobenzoxazepine derivative with an antipsychotic potential, on circulating prolactin levels in male rats
Liégeois, Jean-François ULg; Bruhwyler, J.; Hendrick, J. C. et al

in Neuroscience Letters (2002), 319(1), 49-52

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal ... [more ▼]

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal injection in gentled male rats in comparison with clozapine and haloperidol. A total of 30 or 150 min after administration, whole blood was collected for preparing serum samples. Prolactin was quantified by radioimmunoassay method. At 30 min, JL 13 like clozapine, increased prolactin concentration only at the higher dose (30 mg/kg) while haloperidol at both tested doses induced a dramatic increase of prolactin concentration. At 150 min after injection, only haloperidol (0.3 mg/kg) significantly increased serum prolactin level. This minimal effect on prolactinemia reinforces the similarity of clozapine and JL 13 regarding the atypical antipsychotic profile. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. [less ▲]

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See detailElectrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-Like Analogues
Mouithys-Mickalad, Ange ULg; Kauffmann, J. M.; Petit, C. et al

in Journal of Medicinal Chemistry (2001), 44(5), 769-76

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9 ... [more ▼]

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The oxazepine derivative 7, unlike the other diazepine derivatives (6, 10--12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH(3)O > CF(3)SO(2)O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues. [less ▲]

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See detailHypochlorous Acid, a Major Oxidant Produced by Activated Neutrophils, Has Low Effect on Two Pyridobenzazepine Derivatives, Jl 3 and Jl 13
Liégeois, Jean-François ULg; Zahid, N.; Bruhwyler, J. et al

in Archiv der Pharmazie (2000), 333(2-3), 63-7

JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]- [1,5]benzoxazepine fumarate) and JL 3 (10-(4-methylpiperazin-1- yl)pyrido[4,3-b][1,4]benzothiazepine), two pyridobenzazepine derivatives ... [more ▼]

JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]- [1,5]benzoxazepine fumarate) and JL 3 (10-(4-methylpiperazin-1- yl)pyrido[4,3-b][1,4]benzothiazepine), two pyridobenzazepine derivatives structurally related to clozapine, were selected for further development. Due to their structural similarity to clozapine, they are haunted by the spectre of clozapine-induced agranulocytosis. In a previous study, JL 13 was shown to be less sensitive to oxidation than clozapine. In the present paper, using an in vitro procedure, we report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, on both drugs. It appears that the oxidations of JL 3 and JL 13, unlike clozapine, are very slow and little secondary product is formed. Moreover, in contrast to clozapine, the products that were formed are not reactive and thus do not react with glutathione or N-acetylcysteine. Thus, if, as postulated for clozapine, drug-induced agranulocytosis is due to a reactive metabolite formed by neutrophils or their precursors, JL 3 and JL 13 would not be expected to cause the same adverse reaction. [less ▲]

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See detailOxidation Sensitivity May Be a Useful Tool for the Detection of the Hematotoxic Potential of Newly Developed Molecules: Application to Antipsychotic Drugs
Liégeois, Jean-François ULg; Bruhwyler, J.; Petit, C. et al

in Archives of Biochemistry & Biophysics (1999), 370(1), 126-37

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various ... [more ▼]

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (<70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects. [less ▲]

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See detailComparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.
Bruhwyler, J.; Liégeois, Jean-François ULg; Gerardy, J. et al

in Behavioural Pharmacology (1998), 9(8), 731-7

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic ... [more ▼]

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data. [less ▲]

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See detailFacilitatory effects of chronically administered citicoline on learning and memory processes in the dog.
Bruhwyler, J.; Liégeois, Jean-François ULg; Geczy, J.

in Progress in Neuro-Psychopharmacology & Biological Psychiatry (1998), 22(1), 115-28

1. Citicoline (cytidine (5') diphosphocholine) has been shown to reverse aging-induced memory deficits, scopolamine-induced amnesia and nucleus basalis magnocellularis lesion-induced learning impairment ... [more ▼]

1. Citicoline (cytidine (5') diphosphocholine) has been shown to reverse aging-induced memory deficits, scopolamine-induced amnesia and nucleus basalis magnocellularis lesion-induced learning impairment. 2. This study aimed to evaluate the effects of citicoline on learning and retrieval processes in a complex differential reinforcement of response duration schedule in normal dogs. 3. The effects of citicoline on a stabilized performance were also measured in order to be able to differentiate specific memory effects from non specific influences on the motor, neuro-vegetative and motivational systems. 4. The results demonstrate that citicoline can exert facilitatory effects on learning and memory but also on retrieval processes. The complete absence of effects on the stabilized performance and on the motor, neuro-vegetative and motivational systems constitutes arguments in favour of a selectivity of action on the memory processes. [less ▲]

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See detailDopamine D4 receptors, a new opportunity for research on schizophrenia
Liégeois, Jean-François ULg; Eyrolles, L.; Bruhwyler, J. et al

in Current Medicinal Chemistry (1998), 5

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See detailJl 13, a Potential Successor to Clozapine, Is Less Sensitive to Oxidative Phenomena
Liégeois, Jean-François ULg; Mouithys-Mickalad, Ange ULg; Bruhwyler, J. et al

in Biochemical and Biophysical Research Communications (1997), 238(1), 252-5

The oxidation behaviour of JL 13, a promising antipsychotic, was investigated in comparison with clozapine and loxapine, by measuring their direct "radical scavenging" abilities and their efficacies in ... [more ▼]

The oxidation behaviour of JL 13, a promising antipsychotic, was investigated in comparison with clozapine and loxapine, by measuring their direct "radical scavenging" abilities and their efficacies in inhibiting the lipid peroxidation. In the lipid peroxidation system, the reactivity of these compounds with free radicals produced by gamma-irradiation of linoleic acid may be presented as follows: JL 13 = loxapine < clozapine. In two enzymatic systems (HRP/GSH and HRP/H2O2/ GSH) which generate the thiyl free radicals, clozapine produces a strong enhancement of the thiyl-radical EPR signal intensity while JL 13 and loxapine exhibit no or minimal effect on this signal. The redox potential values for the three derivatives confirm the spectro-photometric and EPR results. Following this study, we show that JL 13, although presenting a preclinical clozapine-like profile, appears less sensitive to oxidation than clozapine. [less ▲]

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See detailDopamine D4 selective ligands as potential antipsychotics
Liégeois, Jean-François ULg; Bruhwyler, J.

in Awouters, Frank (Ed.) Proceedings of the XIVth International Symposium on Medicinal Chemistry (1997)

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See detailJL 13, a pyridobenzoxazepine compound with potential atypical antipsychotic activity: a review of its behavioral properties
Bruhwyler, J.; Liégeois, Jean-François ULg; Bergman, J. et al

in Pharmacological Research (1997), 36

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See detailPirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties.
Bruhwyler, J.; Liégeois, Jean-François ULg; Geczy, J.

in Pharmacological Research (1997), 36(1), 23-33

Pirlindole is a tetracyclic compound that has been characterized as a potential antidepressant drug. It has pharmacological characteristics in common with both tricyclic antidepressants and classical ... [more ▼]

Pirlindole is a tetracyclic compound that has been characterized as a potential antidepressant drug. It has pharmacological characteristics in common with both tricyclic antidepressants and classical irreversible monoamine oxidase inhibitors. Its main mechanism of action consists of a selective and reversible inhibition of monoamine oxidase A. Secondarily, it exerts an inhibitory effect on noradrenaline and 5-hydroxytryptamine reuptakes. It has no effect on the dopaminergic and cholinergic systems. It has only a low potential for amplifying tyramine and noradrenaline pressor effect, which makes one expect that it will not be at the basis of a 'cheese effect'. Pirlindole has an absolute bioavailability of between 20 and 30% due to an extensive first-pass effect. Orally, the Tmax varies between 2.5 and 6 h in the rat and 0.8 and 2 h in the dog. Two phases of elimination (7.5 and 34-70 h) are measured in the rat and three phases in the dog (1.3, 10.8 and 185 h); it is extensively metabolized. The rat eliminates mainly unconjugated products while the dog eliminates mostly conjugated products. Acute and chronic toxicological studies have not revealed potentially dangerous effects of the drug at the usual doses. It does not present measurable mutagenic, clastogenic or carcinogenic properties. Thus, pirlindole shows pharmacological, pharmacokinetic and toxicological properties which make it suitable for the management of depression. [less ▲]

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See detailDiarylazepine derivatives as potent atypical neuroleptic drugs: Recent advances
Liégeois, Jean-François ULg; Bruhwyler, J.; Rogister, F. et al

in Current Medicinal Chemistry (1995), 1

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See detailNew dibenzazepine derivatives with disinhibitory and/or antidepressant potential: neurochemical and behavioural study in the open-field and forced swimming tests.
Bruhwyler, J.; Liégeois, Jean-François ULg; Lejeune, C. et al

in Behavioural pharmacology (1995), 6(8), 830-838

Original bioisosteric analogues of clozapine were evaluated for potential disinhibitory and/or antidepressant effects using the open-field test in the rat and Porsolt's forced swimming test in the mouse ... [more ▼]

Original bioisosteric analogues of clozapine were evaluated for potential disinhibitory and/or antidepressant effects using the open-field test in the rat and Porsolt's forced swimming test in the mouse. Attempts to relate the behavioural results to the binding affinities for dopamine (D1, D2), serotonin (5-HT(2)) and muscarinic (M) receptors were also undertaken. In the open-field test, two main profiles were observed. The first profile corresponded to disinhibitory molecules resembling diazepam and ritanserin. The second profile corresponded to antipsychotic compounds resembling either typical (haloperidol, clothiapine) or atypical (clozapine) neuroleptics. The results obtained in the forced swimming test confirmed the neuroleptic-like activity of the second group of compounds, while two compounds of the first group (JL 3 and JL 26) showed an antidepressant-like activity, JL 3 being as active as imipramine. While it was not possible to relate the first profile to any binding interaction, a relation could be established among the second group of compounds between the typical or atypical antipsychotic behavioural profile and the 5-HT(2)/D2 ratio. [less ▲]

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See detailModulation of the Clozapine Structure Increases Its Selectivity for the Dopamine D4 Receptor
Liégeois, Jean-François ULg; Bruhwyler, J.; Damas, Jacques ULg et al

in European Journal of Pharmacology (1995), 273(3), 1-3

Clozapine has a more marked affinity for the recently cloned dopamine D4 receptor than for the dopamine D2 receptor. In the search for a selective ligand for the dopamine D4 receptor, useful as a ... [more ▼]

Clozapine has a more marked affinity for the recently cloned dopamine D4 receptor than for the dopamine D2 receptor. In the search for a selective ligand for the dopamine D4 receptor, useful as a pharmacological tool or as a potent atypical antipsychotic, a pyridobenzodiazepine derivative bioisoster of clozapine, JL 18, 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine, was found to be the most dopamine D4-selective ligand belonging to the diarylazepine class. Indeed, JL 18 binds to the dopamine D4 receptor with affinity up to 25 times superior to that for the dopamine D2 receptor and presents reduced affinities for other receptors. [less ▲]

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See detailPyridobenzoxazepine and Pyridobenzothiazepine Derivatives as Potential Central Nervous System Agents: Synthesis and Neurochemical Study
Liégeois, Jean-François ULg; Rogister, F. A.; Bruhwyler, J. et al

in Journal of Medicinal Chemistry (1994), 37(4), 519-25

In order to characterize the pharmacological profile of the different chemical classes of pyridobenzazepine derivatives, a series of N-methylpiperazinopyrido[1,4]- and -[1,5]- benzoxa- and benzothiazepine ... [more ▼]

In order to characterize the pharmacological profile of the different chemical classes of pyridobenzazepine derivatives, a series of N-methylpiperazinopyrido[1,4]- and -[1,5]- benzoxa- and benzothiazepine derivatives were prepared. The affinities for D2, D1, 5-HT2, and cholinergic (M) receptors were measured. In comparison to dibenzazepine reference compounds, a strong decrease of the affinities was observed, less pronounced, however, for the substituted analogues. Oxazepine and thiazepine analogues like clozapine (except 8-chloro-6-(4-methylpiperazin-1-yl)-pyrido[2,3-b][1,4]benzoxazepin e (9) and 8-chloro-6-(4-methylpiperazin-1-yl)pyrido[2,3-b][1,4]- benzothiazepine (11)) were found to be inactive against apomorphine stereotypies. In the open-field test in rats, different molecules showed a high disinhibitory activity as observed with anxiolytic drugs. Moreover, 8-chloro-5-(4-methylpiperazin-1-yl)pyrido[2,3-b][1,5]benzoxazepine (14) presented a clozapine-like profile that was confirmed in the behavioral model in dogs and showed most of the behavioral characteristics described for antipsychotic drugs. Its neurochemical profile, in particular the 5-HT2/D2 ratio, was also compatible with atypical antipsychotic activity. [less ▲]

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See detailNew Pyridobenzodiazepine Derivatives as Potential Antipsychotics: Synthesis and Neurochemical Study
Liégeois, Jean-François ULg; Bruhwyler, J.; Damas, Jacques ULg et al

in Journal of Medicinal Chemistry (1993), 36(15), 2107-14

The discovery of a new, safe, atypical antipsychotic remains an important challenge. To achieve this goal, a series of N-methylpiperazinopyrido[2,3-b] [1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5 ... [more ▼]

The discovery of a new, safe, atypical antipsychotic remains an important challenge. To achieve this goal, a series of N-methylpiperazinopyrido[2,3-b] [1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5]- benzodiazepines were synthesized. The dopaminergic (D1, D2), serotonergic (5-HT2), and cholinergic (M) affinities, frequently remarked in the action mechanisms of antipsychotic drugs, were determined using their respective in vitro receptor binding assays. All affinities were reduced for each compound. Optimal substituents were found to be in the 2- or 8-position for the retention of affinities, while substitution at the 5-position by acyl or alkyl groups dramatically diminished binding affinities. Pyridobenzodiazepine derivatives, such as clozapine, were found to be inactive or only weakly effective against apomorphine-mediated stereotypes in rats. In an original and complex behavioral model developed in dogs and successfully used to differentiate distinct classes of psychotropic drugs and to discriminate between typical and atypical neuroleptic drugs, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b] [1,4]benzodiazepine (9), 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine (12), and 5-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,5]benzodiazepine (16) showed most of the behavioral characteristics previously described for neuroleptics. Their neurochemical profiles, particularly their 5-HT2/D2 pKi ratios, were compatible with an atypical antipsychotic effect. These compounds were selected for further investigation. The proposed modulations could lead to new possibilities for the pharmacochemistry of diarylazepines. [less ▲]

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See detailNitric oxide: a new messenger in the brain.
Bruhwyler, J.; Chleide, E.; Liégeois, Jean-François ULg et al

in Neuroscience & Biobehavioral Reviews (1993), 17(4), 373-84

The important role played by nitric oxide (NO) in the central nervous system has largely been emphasized in the recent literature. It can originate at least from four different sources: the endothelium of ... [more ▼]

The important role played by nitric oxide (NO) in the central nervous system has largely been emphasized in the recent literature. It can originate at least from four different sources: the endothelium of cerebral vessels, the immunostimulated microglia and astrocytes, the nonadrenergic noncholinergic nerve, and the glutamate neuron. NO has been implicated in a large number of pathologies (such as neurotoxicity in Alzheimer's disease and Huntington's disease, cerebral ischemia, stroke, and anxiety) and also in normal physiological functions (such as memory and learning, regulation of the cerebrovascular system, modulation of the wakefulness, mediation of nociception, olfaction, food intake and drinking, regulation of noradrenaline, and dopamine release). The aim of this paper is to review and to integrate the most recent advances in our understanding of the roles of NO in the brain. [less ▲]

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See detailComparative study of typical neuroleptics, clozapine and newly synthesized clozapine-analogues: correlations between neurochemistry and behaviour.
Bruhwyler, J.; Liégeois, Jean-François ULg; Chleide, E. et al

in Behavioural pharmacology (1992), 3(6), 567-579

While neuroleptic therapy with classical compounds has frequently been associated with extrapyramidal side effects, clozapine has revealed an interesting antipsychotic profile without producing any ... [more ▼]

While neuroleptic therapy with classical compounds has frequently been associated with extrapyramidal side effects, clozapine has revealed an interesting antipsychotic profile without producing any clearcut motor side effects. However, some adverse reactions remained that stimulated the search for improved antipsychotic agents. The aim of this study was to characterize the behavioural and neurochemical profiles of typical neuroleptics (chlorpromazine, haloperidol), clozapine, and four newly synthesized clozapine-analogues. Affinity for dopaminergic (D1,D2), serotonergic (5-HT(2)) and cholinergic (muscarinic) receptors were measured and the ratios of these different binding affinities were determined and correlated with the behavioural effects of the drugs in a complex temporal regulation task in the dog. The four clozapine-analogues showed most of the behavioural characteristics previously described for neuroleptics and their neurochemical profile, particularly their 5-HT(2)/D2 pKi ratio, was compatible with an atypical antipsychotic effect. Among these drugs, JL5 and JL13 showed a high degree of similarity with clozapine. Like clozapine, they did not induce catalepsy and stereotypy/hyperkinesia. Moreover, other motor effects were also reduced (ataxia, akinesia, dystony). and tremor and sialorrhea were completely absent with these two molecules. [less ▲]

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