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C Pimoule

Publications and source records attributed to C Pimoule.

15 recordsLinked to original sources
PubMed1992

SL 84.0418: a novel, potent and selective alpha-2 adrenoceptor antagonist: in vitro pharmacological profile.

One novel, potent and selective alpha-2 adrenoceptor antagonist is 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2- propylpyrrolo[3,2,1-hi]-indole hydrochloride (SL 84.0418). It inhibits with high affinity the radioligand binding to rat cortical alpha-2 adrenoceptors, as well as to human platelet alpha-2 adrenoceptors labeled with [3H]idazoxan (Ki = 7 nM). SL 84.0418 has low affinity for alpha-1 adrenoceptors labeled with [3H]prazosin (Ki = 3.3 microM). In vitro, SL 84.0418 has no alpha agonist properties, whereas it is a potent alpha-2 adrenoceptor antagonist at both pre- and postsynaptic alpha-2 adrenoceptors. In contrast, it possesses low potency as an antagonist at postsynaptic alpha-1 adrenoceptors demonstrating a more than 1000-fold selectivity toward alpha-2 compared with alpha-1 adrenoceptors. In the same tests, the alpha-2 adrenoceptor antagonist idazoxan had a selectivity ratio of 200. SL 84.0418 is the racemic mixture of two enantiomers, SL 86.0715 [(+) enantiomer] and SL 86.0714 [(-) enantiomer]. The alpha-2 adrenoceptor blocking activities reside with SL 86.0715. Similar to idazoxan, SL 84.0418 increases in a concentration-dependent manner the electrically evoked release of [3H]norepinephrine from rat hypothalamic slices through the blockade of the presynaptic inhibitory alpha-2 adrenoceptors. In isolated hamster adipocytes, SL 84.0418 potently antagonizes the inhibition of lipolysis induced by UK 14,304. In addition, SL 84.0418 inhibits epinephrine-induced aggregation of rabbit platelets, effects mediated by postsynaptic alpha-2 adrenoceptors. SL 84.0418 does not inhibit (IC50 > 1,000 nM) radioligand binding to other receptors or recognition sites, nor does it inhibit calcium, sodium or potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1988

Short-term lithium administration to healthy volunteers produces long-lasting pronounced changes in platelet serotonin uptake but not imipramine binding.

Platelet [3H]-5HT uptake, [3H]-imipramine binding and endogenous 5HT levels were measured in healthy volunteers during short-term (20 days) administration of lithium, and following its withdrawal. The Vmax of [3H]-5HT uptake was significantly decreased during lithium treatment. Following lithium withdrawal, platelet [3H]-5HT uptake (Vmax) remained decreased and was followed by a pronounced rebound effect in some of the subjects for up to 3 months. The affinity constant (Km) of [3H]-5HT uptake was not modified. Binding of tritiated imipramine during the same period and platelet 5HT levels measured till 14 days after withdrawal was not affected by lithium treatment. As lithium is devoid of in vitro effects on both 5HT uptake and imipramine binding, it is concluded that the effects of lithium on the 5HT transporter do not reflect a direct effect on the transporter complex. Our results indicate that lithium-induced changes at the level of 5HT uptake in platelets are not correlated with concomitant variations in platelet 5HT content and can be dissociated from modifications at the level of imipramine binding sites within the macromolecular complex of the 5HT transporter. Moreover, platelet 5HT uptake is apparently modulated by lithium, with a similar pattern in healthy volunteers and in manic-depressive patients.

Adult↗
PubMed1987

[3H]desipramine labels with high affinity the neuronal transporter for adrenaline in the frog heart.

Desipramine, a tricyclic antidepressant, inhibits the neuronal uptake of adrenaline and noradrenaline and, as a radioligand, labels the noradrenaline transporter in central and peripheral tissues of the rat. To study whether [3H]desipramine also labels the neuronal adrenaline transporter in vitro, its binding was evaluated in the frog heart, a tissue with a rich adrenergic innervation but virtually devoid of noradrenergic innervation. [3H]Desipramine binding to membranes from the frog heart was of high affinity (Kd = 1.94 nM) and was potently inhibited by nisoxetine and (+)oxaprotiline. Unexpectedly, [3H]desipramine binding to the transporter for adrenaline in the frog heart was also sensitive to inhibition by imipramine and the atypical antidepressants mianserin and iprindol. This is the first study to demonstrate radioligand binding to the neuronal transporter for adrenaline. The results indicate that the pharmacological profile of the transporter for adrenaline may be different from that of the noradrenergic transporter, if species differences can be excluded. It remains to be established if the affinity of imipramine, mianserin and iprindol for the adrenaline transporter contributes to their therapeutic efficacy in depression.

Animals↗
PubMed1987

Changes in [3H]5-HT uptake and [3H]imipramine binding in platelets after chlorimipramine in healthy volunteers. Comparison with maprotiline and amineptine.

In the platelets of normal healthy volunteers (n = 8) taking chlorimipramine (50 mg/day) for 1 week, the saturable uptake of [3H]5-hydroxytryptamine (5-HT) was fully inhibited at the end of the week, but returned to control values after 2 weeks washout. The Bmax of [3H]imipramine binding was decreased by 63% at the end of the treatment and remained significantly decreased below control values after 1 week washout, whereas the Kd values were increased at the end of the treatment, but had returned to baseline values after 1 week washout. The time course of recovery following the administration of chlorimipramine showed some variation between subjects, but it was necessary to wait up to 4 weeks of washout before the Bmax of [3H]imipramine returned to baseline levels. In contrast, neither 1-week treatment with maprotiline (50 mg/day) nor with amineptine (100 mg/day) changed the parameters of [3H]5-HT uptake or [3H]imipramine binding in platelets from healthy volunteers. These results support the following conclusions. (1) [3H]Imipramine binding in platelets can be down-regulated by relatively low, subtherapeutic doses of chlorimipramine. (2) It is possible to dissociate [3H]imipramine binding parameters from [3H]5-HT uptake because the time course of recovery was clearly different, indicating that [3H]imipramine labels a site linked with, but different from, the 5-HT recognition site in the transporter complex. (3) A washout of antidepressants of 4 weeks may be needed when studying the parameters of [3H]imipramine binding in platelets from depressed patients if the previous medication involved chlorimipramine. For antidepressants like maprotiline or amineptine, that act through mechanisms other than inhibition of 5-HT uptake, the time of washout appears to be less critical, although it is not possible to rule out the existence of some secondary modifications influencing the 5-HT transporter complex.

Adult↗
PubMed1985

Sodium dependent [3H]cocaine binding associated with dopamine uptake sites in the rat striatum and human putamen decrease after dopaminergic denervation and in Parkinsons disease.

The binding of radiolabelled cocaine, an inhibitor of dopamine uptake, to the post-mortem human putamen was studied and compared to that in the rat striatum. Saturation analysis of [3H]cocaine binding to the human putamen revealed the presence of a high affinity component of binding with a Kd of 0.21 mumol/l and a Bmax of 1.47 pmol/mg protein. In addition a low affinity component (Kd = 26.4 mumol/l) was demonstrated, having a Bmax of 42.2 pmol/mg protein. Also in the rat striatum [3H]cocaine binding was both of high affinity (Kd = 0.36 mumol/l, Bmax = 5.56 pmol/mg protein) and low affinity (Kd = 25.9 mumol/l, Bmax = 35.6 pmol/mg protein). A pharmacological characterisation of high affinity [3H]cocaine binding to rat striatal membranes clearly indicates an association with the neuronal dopamine transporter. The IC50 values of 8 selected drugs for inhibition of [3H]cocaine binding in the rat striatum were highly significantly correlated with their potency to inhibit [3H]dopamine uptake into slices of the rat striatum. [3H]Cocaine binding was stereospecifically inhibited by (+)nomifensine and (+)diclofensine which were 50-80-fold more active than their respective (-)isomers. Drugs with dopamine releasing activity were more potent at inhibiting [3H]dopamine uptake than at competing for the high affinity site of [3H]cocaine binding. A highly significant correlation was found between IC50 values for [3H]cocaine binding in the rat striatum and the human putamen. Further evidence in support of an association of [3H]cocaine binding in the rat striatum with the dopamine transporter was obtained from lesion studies. Thus, intranigral 6-hydroxydopamine administration produced a marked (67%) decrease in striatal [3H]cocaine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

[3H]RX 781094: a new antagonist ligand labels alpha 2-adrenoceptors in the rat brain cortex.

[3H]RX 781094 [(imidazolinyl-2)-2 benzodioxane-1,4 [3H]chlorhydrate], a specific alpha 2-adrenoceptor antagonist radioligand, has been used to characterize alpha 2-adrenoceptors in rat cortical membranes. [3H]RX 781094 binding is reversible, saturable and stereospecific. It labels with high affinity a single population of non-interacting sites. The KD value was 3.9 +/- 0.4 nM and the Bmax 189.0 +/- 12.4 fmol/mg protein. Competition curves with different alpha-adrenoceptor agonists and antagonists showed that the binding sites labelled with [3H]RX 781094 had the pharmacological characteristics of alpha 2-adrenoceptors. Pretreatment with reserpine (2.5 mg/kg s.c., 24 h before the experiment) did not affect the KD or Bmax values of [3H]RX 781094 binding. Chemical destruction of noradrenergic pathways by systemic injection of DSP4 or intracerebral injection of 6-hydroxydopamine did not modify the KD or the Bmax of [3H]RX 781094 binding. It is concluded that the major proportion of alpha 2-adrenoceptors labelled with [3H]RX 781094 are not localised to noradrenergic nerve terminals.

Adrenergic alpha-Antagonists↗
PubMed1983

3H-Rauwolscine binding in platelets from depressed patients and healthy volunteers.

3H-Rauwolscine binds specifically and with high affinity to alpha 2-adrenoceptors in human platelets. In a study comparing the binding of 3H-rauwolscine in platelets obtained from 26 control volunteers with 19 hospitalised, untreated, severely depressed patients, the mean maximal binding (Bmax) and mean dissociation constant (Kd) of 3H-rauwolscine binding were found to be identical in both groups. After 7-12 days, treatment with different tricyclic antidepressant drugs there was a significant improvement in the depressive symptoms but no change in the 3H-rauwolscine binding. After an average of 23 days treatment with tricyclic antidepressants, and when the Hamilton Depression Rating Scores had returned to normal, the Kd and Bmax of 3H-rauwolscine binding were still unchanged.

Adjustment Disorders↗
PubMed1982

High-affinity [3H]desipramine binding in the peripheral and central nervous system: a specific site associated with the neuronal uptake of noradrenaline.

The specific binding of [3H]desipramine to various brain regions and peripheral tissues of the rat was of high affinity, rapid and reversible. It was inhibited with high affinity only by tricyclic antidepressants and noradrenaline uptake blockers. There was a highly significant correlation between the potencies of a series of drugs for the inhibition of [3H]desipramine binding and for the inhibition of noradrenaline uptake. Substrates for the noradrenaline uptake system however inhibited the binding of [3H]desipramine only at very high concentrations. Postganglionic sympathetic denervation of the submaxillary gland and the heart both resulted in a pronounced decrease in [3H]desipramine binding sites, which paralleled the reduction in endogenous noradrenaline levels. High-affinity [3H]desipramine binding sites thus appear to be localised on noradrenergic nerve endings and are probably closely associated with the neuronal uptake system for noradrenaline.

Animals↗
PubMed1979

GABA metabolism in cultured glial cells.

GABA-transaminase has been characterized in cultured astrocytes. It is identical to the synaptosomal and perikaryal enzyme in terms of charge, molecular weight, and stability, but it differs in its affinity for GABA, which is much higher in the glial compartment. GABA-transaminase has been shown to be inducible by high GABA concentrations, which suggests that astrocytes have the possibility not only to transport GABA but also to metabolize the amino acid which is taken up.

4-Aminobutyrate Transaminase↗