Biomedical subjects

Abdeslam Chagraoui

Publications and source records attributed to Abdeslam Chagraoui.

5 recordsLinked to original sources

PubMed2005

Structure-affinity relationships of halogenated predicentrine and glaucine derivatives at D1 and D2 dopaminergic receptors: halogenation and D1 receptor selectivity.

Halogenation of the aporphine alkaloid boldine at the 3-position leads to increased affinity for rat brain D(1)-like dopaminergic receptors with some selectivity over D(2)-like receptors. A series of 3-halogenated and 3,8-dihalogenated (halogen=Cl, Br or I) derivatives of predicentrine (9-O-methylboldine) and glaucine (2,9-di-O-methylboldine) were prepared and assayed for binding at D(1) and D(2) sites. Halogenation of predicentrine led to strong increases in affinity for D(1)-like receptors, while the affinities for D(2)-like receptors were either practically unchanged or reduced three- to fourfold. Halogenated glaucine derivatives did not show any clear trend towards enhanced selectivity, and the affinities were poor and similar to or worse than the values previously recorded for glaucine itself. Together with earlier work on boldine derivatives, these results suggest that the 2-hydroxy group on the aporphine skeleton may determine a binding mode favoring D(1)-like over D(2)-like receptors, with enhanced affinity when the C-3 position is halogenated.

Animals↗

PubMed2004

Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure.

BACKGROUND: Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O2 supply, and reduces myocardial O2 consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown. METHODS AND RESULTS: We assessed, in rats with CHF, the effects of long-term HRR induced by the selective I(f) current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (-18% versus untreated at 10 mg x kg(-1) x d(-1)), without modifying blood pressure, LV end-diastolic pressure, or dP/dt(max/min). Ivabradine significantly reduced LV end-systolic but not end-diastolic diameter, which resulted in preserved cardiac output due to increased stroke volume. In the Langendorff preparation, ivabradine shifted LV systolic but not end-diastolic pressure-volume relations to the left. Ivabradine decreased LV collagen density and increased LV capillary density without modifying LV weight. Three days after interruption of treatment, the effects of ivabradine on LV geometry, shortening, and stroke volume persisted despite normalization of heart rate. CONCLUSIONS: In rats with CHF, long-term HRR induced by the selective I(f) inhibitor ivabradine improves LV function and increases stroke volume, preserving cardiac output despite the HRR. The improvement of cardiac function is related not only to the HRR per se but also to modifications in the extracellular matrix and/or function of myocytes as a consequence of long-term HRR.

Animals↗

PubMed2003

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats.

Agomelatine, an antidepressant with melatonin agonist and 5-HT(2C) antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1-naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy-7-methoxynaphtalen-1-yl)ethyl]acetamide), have been assessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT(2C) receptors and their effects on inositol phosphate production. These compounds were also tested for their ability to inhibit the penile erections induced by the 5-HT(2C) receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT(2C) receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175-induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT(2C) receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175-induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agomelatine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT(2C) receptor antagonist properties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine.

Acetamides↗

PubMed2003

Effects of some antioxidative aporphine derivatives on striatal dopaminergic transmission and on MPTP-induced striatal dopamine depletion in B6CBA mice.

(S)-(+)-boldine, an aporphine alkaloid displaying antioxidative and dopaminergic properties, and six of its derivatives (glaucine, 3-bromoboldine, 3-iodoboldine, 8-aminoboldine, 8-nitrosoboldine and 2,9-O,O'-dipivaloylboldine) were tested for these properties in comparison with their parent compound. All the tested compounds displayed in vitro antioxidative properties equal to or slightly weaker than those of boldine, and equal to or stronger than (+/-)-6-hydroxy-2,5,7,8,-tetramethylchromane-2-carboxylic acid (Trolox), a water-soluble vitamin E analogue, used as a reference compound. All the aporphine compounds tested displaced [3H]SCH 23390 and [3H]raclopride from their specific binding sites in rat striatum. When tested on dopamine (DA) metabolism in the striatum of B6CBA mice, all the compounds, except 8-aminoboldine, increased striatal levels of DOPAC and HVA, and the HVA/DA ratio, indicating that they cross the blood-brain barrier and that they seem to act as dopamine antagonists in vivo. B6CBA mice were sensitive to the neurotoxic action of MPTP on dopaminergic neurons as indicated by the strongly decreased striatal levels of DA, DOPAC and HVA following administration of MPTP (20 mg/kg, i.p.). Among these aporphine derivatives, only 3-bromoboldine was able to reduce the MPTP-induced decrease of striatal levels of DA and DOPAC, whereas (R)-apomorphine (5 mg/kg, s.c.) and acetylsalicylic acid (100 mg/kg, i.p.), used as reference compounds, were very active. These data suggest that potent in vitro antioxidative properties and the ability to cross the blood-brain barrier are not sufficient criteria to predict the inhibition of neuronal degeneration induced by MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2002

Tissue Doppler imaging differentiates physiological from pathological pressure-overload left ventricular hypertrophy in rats.

BACKGROUND: The myocardial velocity gradient (MVG) is a recent index of regional myocardial function derived from endocardial and epicardial velocities obtained by tissue Doppler imaging (TDI). This index might be useful for discriminating between physiological and pathological left ventricular hypertrophy (LVH) and for documenting the early transition from compensated LVH to heart failure. We sought to compare MVG measured across the left ventricular posterior wall between normal rats and rats with physiological (exercise) and pathological (pressure-overload) LVH. METHODS AND RESULTS: Wistar rats were assigned to one of the following groups: sedentary, exercise (swimming), and 2-month or 9-month abdominal aortic banding. Compared with sedentary rats, exercise and 2-month banding led to similar and significant LVH. After 2-month banding, conventional parameters of systolic function (left ventricular fractional shortening and dP/dt(max)) were not affected. However, systolic and diastolic MVG were similar in exercise and sedentary rats but were significantly lower in rats with aortic banding. Aortic debanding after 2 months led to a full recovery of MVG, whereas MVG remained decreased when debanding was performed after 9 months. CONCLUSIONS: Myocardial contraction and relaxation assessed by TDI were impaired in pressure-overload LVH but not in exercise LVH. Therefore, TDI is more sensitive than conventional echocardiography for assessing myocardial dysfunction in pressure-overload LVH and for predicting early recovery in myocardial function after loading conditions normalization.

Animals↗