François Huguet

Synthèse et propriétés pharmacologiques de quelques thiéno[2,3-d]pyrimidin-4-one 2-thiones

The condensation of substituted 2-amino-3-carbethoxy-thiophenes with methyl, ethyl and phenyl isothiocyanate yields the corresponding thienylthioureas which cyclize in ethanol saturated with dry hydrochloric acid to form 3-substituted thieno [2,3-d]pyrimidin-4-(3H)-one-2-thiones. Thirty-five compounds, 21 thienylthioureas and 14 thienopyrimidin-4-one-2-thiones have been screened for their analgesic and anti-inflammatory activities. The ip administration of these products at a dose of 1000 mg/kg shows that they are not toxic (one excepted). Some compounds show analgesic and anti-inflammatory activities equivalent to those of acetylsalicylic acid.

Synthèse et propriétés pharmacologiques de quelques thiénopyrimidones-4 substituées

The synthesis of two series of substituted thieno[2,3-d]pyrimidine-4-ones is described. Analgesic and anti-inflammatory properties of these 18 compounds were investigated. Most of them showed very low toxicity. Seven compounds exhibited significant analgesic activity, six compounds displayed an anti-inflammatory activity. Some possessed both effects at levels close to those exhibited by acetylsalicylic acid.

Central interactions between dihydropyridines and cholinergic systems in the control of blood pressure in rat

Intracerebroventricular (i.c.v.) injection of the 1,4-dihydropyridine (DHP) calcium channel agonist, Bay K8644 (30 micrograms/kg) increased mean blood pressure and the K+-evoked release of [3H]acetylcholine ([3H]ACh) from hippocampal slices in spontaneously hypertensive rats (SHR). The Bay K8644-induced hypertension was inhibited by a pretreatment with methylatropine (80 micrograms/kg i.c.v.). In SHR, nicardipine, a DHP calcium channel antagonist, reduced mean blood pressure when i.c.v. injected (10 micrograms/kg). The nicardipine-induced hypotension was reduced by a pretreatment with hemicholinium-3 (20 micrograms, i.c.v.). Nicardipine (1 microM) did not modify, in SHR, the K+-evoked release of [3H]ACh, but inhibited the Bay K8644-induced increase in the ACh release. In normotensive rats, neither Bay K8644 nor nicardipine modify blood pressure, when centrally injected, or the stimulated release of [3H]ACh from hippocampal slices. The participation of central DHP sites in the cholinergic transmission in genetic hypertension is discussed.

Characterization of dihydropyridine binding sites in the rat brain: hypertension and age-dependent modulation of [3H](+)-PN 200-110 binding

The properties of [3H]dihydropyridine (DHP), nitrendipine and (+)-PN 200-110, binding to rat cerebral membranes were investigated. In normotensive Wistar-Kyoto (WKY) adult rats, the highest densities of [3H]DHP binding sites were found in the hippocampus. Frontal cerebral cortex and hypothalamus had intermediate levels and no specific binding of [3H]DHP and [125I]iodipine could be detected in the brainstem membranes and more precisely in the nucleus tractus solitarius and in the locus coeruleus. Changes in the maximal number of DHP binding sites (Bmax) were observed in spontaneously hypertensive rats (SHR) and in old Sprague-Dawley rats. In adult SHR, there was a significant increase in the Bmax values of [3H](+)-PN 200-110 binding in the hippocampus when compared to the values obtained in WKY. There was no difference in the Bmax values between young (3 weeks) prehypertensive SHR and age-matched WKY. In senescent (26 months) Sprague-Dawley rats, the Bmax values of [3H](+)-PN 200-110 binding were significantly reduced (30%) in the frontal cerebral cortex and the hippocampus, as compared with the number of DHP binding sites found in mature Sprague-Dawley rats (15 weeks).

Central α1-adrenoceptors and cardiovascular control in normotensive and spontaneously hypertensive rats

Intracerebroventricular (i.c.v.) injection of AR-C239 (30 μg/kg), a selective α1-adrenoceptor blocking drug, did not modify the heart rate in normotensive control (without pretreatment), bilaterally vagotomized and β blocked rats and in spontaneously hypertensive (SH) bilaterally vagotomized rats. Intracisternal (i.c.) administrations of AR-C 239 (30 μg/kg) however decreased the heart rate in normotensive β blocked and in SH bilaterally vagotomized rats. The differential effect of heart rate on i.c.v. versus i.c. administration of AR-C 239 suggests a brainstem localization of the α1-adrenoceptors involved. The binding of [3H]prazosin was significantly higher in homogenates from whole brain and in membranes from the cerebral cortex and hypothalamus of SH rats as compared to normotensive rats. In addition, the binding of [125I]BE 2254, a new iodinated radioligand of high specific radioactivity used to characterize α1-adrenoceptors, was significantly increased in membranes from the NTS of SH rats. These results suggest that central α1-adrenoceptors localized in the brainstem and in the hypothalamus and the cortex play a role in the control of vagal tone in normotensive rats and of sympathetic activity in SH animals. Thus, it is postulated that central α1-adrenoceptors may participate in either the genesis or the maintenance of genetic hypertension.

Aluminum L-glutamate complex in rat brain cortex: in vivo prevention of aluminum deposit by magnesium D-aspartate.

Our previous experiments in the rat showed that aluminum L-glutamate complex (Al L-Glu) crosses the blood-brain barrier and accumulates in selective brain areas and that Al salts may increase D-aspartic acid forms in living brain proteins, probably by inducing more thermodynamically stable structures than L isomers. As magnesium blocks NMDA receptors, D-aspartic acid was used in the present study in the form of magnesium salt to prevent the excitotoxicity of dicarboxylic amino acids. Effects on brain amino acids and Al cortex levels in mature rats were studied after chronic treatment with Al L-Glu or Na L-Glu alone or in association with magnesium D-aspartate (Mg D-Asp). Results demonstrate that treatment with Mg D-Asp induces a decrease in the Al concentration in brain cortex of Al L-Glu-treated rats. In aluminum-free treated controls, treatment with Mg D-Asp in association with Na L-Glu also induces a decrease in Al concentration in brain cortex. These data indicate that Mg D-Asp administration protects rat brain cortex from Al accumulation and suggest that this treatment may be useful in preventing brain Al intoxication.

Progressive alteration of neuronal dopamine transporter activity in a rat injured by an intranigral injection of MPP

MPTP or its metabolite MPP+ are used to produce a Parkinsonism syndrome in a variety of animal species. The present study describes the effects of intranigral MPP+ administration either at 10 or 40 microg on the neuronal dopamine transporter (DAT) activity measured in rat striatal synaptosomes at different times after lesion. The 40 microg MPP+ injection induced a maximal toxic effect on day 7. However, 10 microg MPP+ progressively inhibited DA uptake on the injured side. V(max) decreased in a time-dependent manner and the lowest value was observed on day 21 after lesion. At this time, the K(m) value began to increase and was continuously accentuated until day 45 as compared to the contralateral side. Treatments either with the antioxidant alpha-tocopherol acetate or the MAO inhibitor pargyline, given daily for 7 days after lesion, partially prevented the 40 microg MPP(+)-induced inhibition of DA uptake. Conversely, both treatments given daily for 21 days after lesion completely prevented the alteration of DAT activity in the ipsilateral striatum induced by 10 microg MPP+. The absence of protection when both treatments were stopped 2 weeks before DA uptake measurements indicated that free radicals and DA oxidized products were continuously accumulated and gradually affected the functionality of the DAT. These results demonstrate that a rat intranigral lesion with 10 microg MPP+ led to a progressive impairment of DAT activity.

Interaction between central α1- and α2-adrenoceptors on sympathetic tone in rats

The interaction between piperoxan and alpha 2-agonists on sympathetic tone was studied in rats. The sympatho-inhibitory effect of alpha 2-agonists (clonidine, guanfacine, B-HT 933) was assessed by recording heart rate in normotensive bilaterally-vagotomized rats. Clonidine (3 micrograms/kg, i.c.v.) and B-HT 933 (100 micrograms/kg, i.c.v.) induced a bradycardia which was fully reversed by piperoxan (30 micrograms/kg, i.c.v.). However, in rats treated with guanfacine, piperoxan induced a partial recovery of the bradycardic effect. The injection of a small dose of the specific alpha 1-adrenoceptor blocking drug, AR-C 239 (10 micrograms/kg, i.c.v.) which, by itself did not modify heart rate, completely inhibited the reversal effect of piperoxan in rats treated with clonidine, B-HT 933 or guanfacine. In rat brainstem membranes, B-HT 933 was found to bind to both alpha 1- and alpha 2-adrenoceptors and was as potent as clonidine in competing for alpha 1-sites bound by [3H]prazosin. On the other hand, in bilaterally vagotomized rats, piperoxan (30 micrograms/kg, i.c.v.) induced an increase in blood pressure and heart rate which was inhibited by previous administration of AR-C 239 (10 micrograms/kg, i.c.v.). These data suggest that, by inhibiting central alpha 2-adrenoceptors, piperoxan unmasks central alpha 1-adrenoceptor stimulation by endogenous catecholamines leading to an increase in the sympathetic tone, but a full recovery in heart rate could be observed only with the mixed alpha 1- and alpha 2-adrenoceptor agonists, clonidine and B-HT 933. In addition, these data further indicate that alpha 1-adrenoceptors are implicated in a tonic control of the sympathetic nerve activity in normotensive rats.

Synthesis, binding affinity and antioxidant activity of new 1,4-dihydropyridines

Abstract The synthesis and in vitro pharmacology of a series of triaryl-1,4-dihydropyridines were investigated. Molecules containing a nitro group on the phenyl ring had a higher affinity for specific [ 3 H](+)-PN 200-110 binding sites. All the compounds possessed a radical scavenging effect and an antiperoxidant activity. These properties were more marked for molecules with 2-pyridinyl and 2-thienyl substituents. The synthesis of new triaryl-1,4-dihydropyridines with both a higher binding affinity and antioxidant activity might be effective in cerebral ischemic disease treatment.

Central α1-adrenergic and opiate systems in the control of the vagal tone in normotensive and spontaneously hypertensive rats

Abstract In anesthetized, normotensive β-blocked rats, the α1-adrenoceptor blocking drug, AR-C 239 (300 μg/kg, i.v.) induced a bradycardic effect related to a central increase in the vagal tone. This bradycardia was inhibited by previous administration of naloxone, intravenously (1 mg/kg) or centrally (100 μg/kg, i.c.) injected. Naloxone, by itself did not change the heart rate. In brainstem membranes from normotensive rats, AR-C 239 did not influence the stereoselective binding of [3H]naloxone. In spontaneously hypertensive (SH) rats, naloxone peripherally or centrally administered did not influence the activation of the vagal tone induced by AR-C 239, in β-blocked animals. These results suggest the possible involvement of opiate release in the AR-C 239-induced vagal bradycardiac, in normotensive rats. They also afford new arguments for the existence of close interactions between central α-adrenergic and opiate systems in the cardiovascular regulation. The possible participation of κ-receptors in this effect is discussed. In addition, such an opiate mechanism triggered by central α1-adrenoceptor blockade seems to be either absent or inactive in SH rats.