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Biomedical subjects

A Uzan

Publications and source records attributed to A Uzan.

At least 73 records · Page 4Linked to original sources
PubMed1984

Pharmacological evidence that PK 8165 behaves as a partial agonist of brain type benzodiazepine receptors.

PK 8165, a new quinoline derivative, has a good affinity for brain type benzodiazepine binding sites and an anticonflict activity in the Vogel Test. However, contrarily to classical benzodiazepines (BZ) this compound is devoid of anticonvulsant and sedative properties. As biochemical studies suggested that PK 8165 is a partial agonist for BZ receptors, its interactions with convulsant, sedative and muscle relaxant properties of diazepam (DZ) were investigated. PK 8165 potentiates (12.5 to 50 mg/kg i.p.) the antagonistic effect of DZ on M.E.S.-induced seizures and footshock-induced fighting in mice. Moreover, PK 8165 potentiates in the same dose range the muscle relaxant and hypnotic effects of DZ in mice. These potentiations are specific since PK 8165 does not interfere with phenobarbital and mebubarbital effects in M.E.S. and righting reflex in mice. Also, PK 8165's anticonflict activity (punished drinking in thirsty rats) is antagonized by RO15-1788, a specific antagonist of centrally active BZ.

Aggression↗
PubMed1984

The 5-hydroxytryptamine-releasing properties of two epimer quinoline derivatives.

Two epimer quinoline derivatives, PK 5078 and PK 7059, have been shown to be potent at releasing 5-HT from blood platelets. Moreover PK 5078 was also a potent and selective inhibitor of the uptake of 5-HT, being about 20 times as active as clomipramine. Both drugs, like p-chloroamphetamine, released 5-HT but did not inhibit MAO-A. Whilst p-chloroamphetamine seemed to be active on the cytoplasmic pool of 5-HT and reserpine on the vesicular pool, PK 5078 and PK 7059 were effective first on the vesicular pool and then on the cytoplasmic pool. The quinoline derivatives were devoid of the typical side-effects of amphetamine-like drugs, i.e. hyperactivity, anorexia and group toxicity. For these reasons PK 5078 and PK 7059 can be considered to be a new type of selective 5.HT-releasing drug.

Animals↗
PubMed1983

Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195, by thermodynamic studies.

The [3H]PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide, binding sites in rat cardiac membranes are saturable, with high affinity, specific GABA-independent and correspond to the peripheral type of benzodiazepine. The order of potency of displacing agents was: PK 11195 greater than RO5-4864 greater than dipyridamole greater than diazepam greater than clonazepam. The Bmax obtained with [3H]PK 11195 was equivalent of the Bmax obtained with [3H]RO5-4864 in the same experimental conditions. However thermodynamic analysis indicates that the [3H]PK 11195 binding was entropy driven whereas the [3H]RO5-4864 binding was enthalpy driven. Consequently PK 11195 might be an antagonist of these binding sites and RO5-4864 an agonist or a partial agonist. The simultaneous use of both drugs might help to elucidate the physiological relevance of peripheral benzodiazepine binding sites.

Animals↗
PubMed1983

A subacute treatment of L-methionine induces an increase in the number of [3H]spiperone binding sites in the striatum of the rat.

A subacute treatment, 500 mg/kg I.P. twice daily during 5 days, by L-methionine provoked an increase in the Bmax of [3H]-spiperone binding in the striatum of the rat. This increase was associated to a decrease in membrane microviscosity. However in these conditions no changes were found in the [3H]-DHA, [3H]QNB bindings or in the brain dopamine sensitive adenylate cyclase activity. L-methionine treatment reduced the accumulation of Dopa after NSD 1015 and antagonized the decrease in striatal acetylcholine provoked by haloperidol. Thus L-methionine might be a new potential drug for Parkinson's disease treatment.

Animals↗
PubMed1983

Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies.

[3H] RO5-4864 binding sites have been characterized in kidney, heart, brain, adrenals and platelets in the rat. In all these organs the following order of potency in the RO5-4864 displacement was found: RO5-4864 greater than diazepam greater than clonazepam indicating that they correspond to the "peripheral type" of benzodiazepine binding sites. PK 11195, an isoquinoline carboxamide derivative, displaces [3H] RO5-4864 from its binding sites in all the organs. PK 11195 was as potent as RO5-4864 in the platelets, heart, adrenals, kidney and several brain regions (midbrain, hypothalamus, medulla + pons and hippocampus. However it was 5 to 10 times more effective in cortex and striatum. In conclusion PK 11195 might represent a new tool to elucidate the physiological relevance of "peripheral type" benzodiazepine binding sites and might help to discriminate the hypothetical subclasses of these binding sites.

Adrenal Glands↗
PubMed1983

Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide. II. In vivo studies.

Peripheral type of benzodiazepine binding sites were labelled in the kidney, the heart and the brain with [3H] RO5-4864 following intravenous injection in mice. The regional distribution of this in vivo binding parallels the in vitro binding: heart and kidney were more labelled than brain. Benzodiazepine potencies in reducing [3H] RO5-4864 binding in vivo parallel relative affinities for [3H] RO5-4864 binding sites in isolated organs membranes: RO5-4864 greater than diazepam greater than clonazepam. PK 11195 a new compound, chemically unrelated to benzodiazepines, which is a potent inhibitor of [3H] RO5-4864 in vitro is also very effective (more than RO5-4864) after I.P. injection and oral administration. These results emphasize the feasibility of using this technique to examine the effects on various pharmacological and physiological manipulations of these binding sites in vivo. Moreover the fact that PK 11195 binds to these sites in vivo might indicate that this compound could help to elucidate the physiological relevance of the peripheral type of benzodiazepine binding sites.

Animals↗
PubMed1983

[3H]spiroperidol binding on lymphocytes: changes in two different groups of schizophrenic patients and effect of neuroleptic treatment.

[3H]spiroperidol binding to lymphocytes was measured in untreated paranoid or disorganized and treated paranoid schizophrenic patients. An increase in the Bmax was detected in untreated paranoid patients but a decrease was found in the disorganized patients. No difference was detected in the KD value. Neuroleptic treatment produced a decrease in the Bmax without affecting the KD value. Such results did not comply with the down regulation but might be explained by a change in membrane viscosity as [3H]spiroperidol binding sites on lymphocytes were coupled to phospholipid methylation.

Adult↗
PubMed1983

Detection of binding sites for spiroperidol on leukemic cells: its value for the phenotype characterization of lymphoid leukemias.

The specific binding of the dopamine antagonist spiroperidol was studied in leukemic cell samples of various phenotypes. Among these only B-cell samples from chronic lymphocytic leukemias (7/7) and some "null" cell samples from acute lymphoblastic leukemias (2/7) showed specific binding. B cells from a prolymphocytic leukemia were negative as were also T-lymphoïd and non-lymphoïd leukemic cells at different stages of maturation. This pattern can be clearly correlated with the previous results obtained with normal blood cells and on cell lines. Moreover, it suggests that the detection of spiroperidol binding sites could provide a new means of distinguishing different phenotypes among B cells and early lymphoïd cells. Our results open the way to further studies which might show a correlation between spiroperidol binding sites and the new immunological markers defining subsets among non-T lymphoïd cells, as well as defining their physiological meaning.

Butyrophenones↗
PubMed1983

Labelling of "peripheral-type" benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization.

PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide] is a new ligand for the "peripheral-type" benzodiazepine binding sites, chemically unrelated to benzodiazepines. It displaces with a very high potency (IC50 congruent to 10(-9) M) [3H]-RO5-4864 (a benzodiazepine which specifically labels the peripheral-type sites) from its binding sites. [3H]PK 11195 binds to a membrane fraction from rat brain cortex and rat olfactory bulb in a saturable and reversible manner with a very high affinity (KD = 10(-9) M). The number of maximal binding sites was ten times greater in the olfactory bulb than in the brain cortex. The order of potency of several compounds as displacers at 25 degrees C (PK 11195 greater than RO5-4864 greater than diazepam greater than dipyridamole greater than clonazepam) demonstrates that [3H]PK 11195 binds to the peripheral-type benzodiazepine binding sites. The KD value for the [3H]PK 11195 binding is not affected by temperature changes, whereas RO5-4864 and diazepam affinities decrease with increasing temperatures. Autoradiographic images of [3H]PK 11195 binding to rat brain sections show that binding sites are mainly localized in the olfactory bulb, median eminence, choroid plexus, and ependyma. This ligand could be a useful tool to elucidate the physiological and pharmacological relevance of these binding sites.

Animals↗
PubMed1983

Evidence for an increase in [3H]spiperone binding in hypothalamic nuclei during the development of spontaneous hypertension in the rat.

The in vivo binding of [3H]spiperone was measured in discrete areas of the hypothalamus in 7, 9 and 16 weeks old spontaneously hypertensive rats (SHR) and age matched normotensive Wistar Kyoto (WKY) controls. The specific binding of [3H]spiperone was significantly higher in the four different hypothalamic regions (H1, H2, H3, H4) that we have tested in 7 or 9 weeks old SHR than in age matched WKY controls. At 16 weeks a significant increase was only present in H3. These results suggest that dopaminergic hypothalamic neurons might be implicated in the onset of hypertension in the rat.

Animals↗
PubMed1983

"Peripheral type" benzodiazepine binding sites in rat adrenals: binding studies with [3H]PK 11195 and autoradiographic localization.

PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinec arboxamide] is a compound chemically unrelated to benzodiazepines with a high affinity for the "peripheral type" binding sites for benzodiazepines (Le Fur et al., 1983a). [3H]PK 11195 binds to the adrenal membranes with a high affinity (KD congruent to 3 nM) in a specific, reversible and GABA-independent manner. Binding is also characterized by very high Bmax (34 pmol/mg protein). These binding sites are the "peripheral type" benzodiazepine binding sites as demonstrated by the potency order of displacement of the [3H]PK 11195 bound: PK 11195 greater than R05-4864 greater than diazepam greater than dipyridamole greater than clonazepam. The biochemical characteristic of the binding to rat adrenal sections has also been studied. In these conditions the affinity for [3H]PK 11195 is ten times smaller, but the potency order of displacing agents was the same, demonstrating the identity of the section binding sites. Using tritium sensitive film these sites have been visualized in adrenal sections. [3H]PK 11195 binding sites are localized in the adrenal cortex with some spare labelling in the medulla.

Adrenal Glands↗
PubMed1983

1-[4-(2-ter-butyl-quinolyl)]-3-(4-piperidyl)propanol (PK 10139): a new potent and long-acting antiarrhythmic agent.

PK 10139 is a new synthetic quinoline antiarrhythmic agent 10 times more potent and at least 2 to 3 times longer acting than quinidine sulfate. In the dog, the near 100% active dose (1.5 mg/kg i.v.) completely converted to sinus rhythm ouabain-induced ventricular tachycardia for over 30 min. The efficacy of this compound against multifocal beats induced by two-stage ligation of the left coronary artery (Harris) in the conscious dog was demonstrated after i.v. and oral administration with no peripheral and central nervous system side effects after the higher effective dose contrary to quinidine. In the anesthetized dog, PK 10139 like quinidine, increased atrial, atrioventricular nodal and ventricular refractory periods as determined with the programmed extrastimulus technique. PK 10139 also increased electrical stimulus threshold and intracardiac conduction times evaluated by measurement of A-H nodal conduction time, H-V conduction time and QRS interval as seen with all the class I antiarrhythmic agents. Thus, PK 10139 is a much more potent and long-acting agent than quinidine, with better tolerance.

Animals↗
PubMed1982

On the long acting gastric antisecretory activity of LM 24056 a non H2 antagonist.

LM 24056, a phenothiazine derivative with no central effects, can be classified as a non anti H2 antisecretory agent with a long duration of action. Its activity was demonstrated orally at low dose in pentagastrin stimulated Shay rat and in Heidenhain pouch in dog against gastrin, pentagastrin, carbachol and test meal. LM 24056 possesses very weak affinity to muscarinic receptors in vitro and in vivo. It has negligible anticholinergic properties in rats and mice at the peripheral level but no effect at the central level. The long lasting antisecretory action of LM 24056 may be supported by the persistent presence in plasma of a desmethyl metabolite at higher concentrations than that of LM 24056 at any time. Contrary to LM 24056 sulfoxide and LM 24056 sulfone, desmethyl LM 24056 is a more potent antisecretory drug than LM 24056. Desmethyl LM 24056 possesses more marked affinity to peripheral muscarinic receptor than LM 24056. As the administration of therapeutic doses of LM 24056 was not followed by anticholinergic side-effects, it may be suggested that LM 24056 activity is related to a "prodrug like effect". Finally the activity of LM 24056 may be related to LM 24056 itself and/or a desmethyl metabolite.

Animals↗
PubMed1982

2-Amino-6-chloro-4-(N-methylpiperazino)pyrimidines, inhibitors of spiroperidol binding.

A series of 30 6-chloro-2,4-diaminopyrimidines was synthesized and tested in vitro as inhibitors of [3H]spiroperidol binding. The affinity for the dopamine receptor was shown to be related to the 6-chloro-4-(N-methyl-piperazine)pyrimidine structure bearing a NH2 or NHR1 group as a substituent in position 2, provided that R1 was not an alpha branched alkyl group. The nature of the substituent in position 5 is also of importance for the affinity; 2-(benzylamino)-6-chloro-4-(N-methylpiperazino)-5-(methylthio)pyrimidine (22) is the most active member of the series. Molecular structures of three compounds were analyzed by X-ray diffraction and PCILO computation.

Animals↗
PubMed1982

[Proserotoninergic agents and depression (author's transl)].

The proserotoninergic hypothesis of depression has been for a long time founded on biochemical parameters (brain from suicide patients, CSF and plasma from depressed patients) or more recently on measurement of platelets 5-HT uptake or imipramine binding. New specific proserotoninergic agents confirm this hypothesis since indalpine, a specific 5-HT uptake inhibitor, has a neurochemical and pharmacological profile characteristics of proserotoninergic agents and is effectively antidepressant in human. 5-HT uptake inhibition seems an important property because when we compared two isomers one, a 5-HT uptake inhibitor and at the same time 5-HT releaser, and the other only releaser, we observed that the first has experimental properties similar to indalpine whereas the second has not the classical spectrum of a proserotoninergic agent.

Animals↗
PubMed1982

[L-Methionine treatment of Parkinson's disease: preliminary results].

Eleven patients with previously untreated Parkinson's disease were treated with L-Methionine for periods from 2 weeks to 6 months. The treatment was well supported and good improvement in clinical signs, particularly akinesia and rigidity, appeared within approximately three weeks, the effect on tremor being less marked. Therapeutic effects were similar to those observed with L-dopa treatment. Correlation of clinical effects with a marked increase in the number of 3H-Spiroperidol binding sites (Bmax) to lymphocytes was noted. This therapeutic effect suggests the role played by modifications of membrane fluidity on dopaminergic receptors, both lymphocytic and striatal, in the etiology of Parkinson's disease, and opens up new therapeutic possibilities in this disease.

Aged↗