1,721,058 research outputs found
Tricyclic pyrazoles. Part 3. Synthesis, biological evaluation and molecular modelling of analogues of the cannabinoid antagonist NESS 0327
No full textA series of analogues of 8-chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo- [6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 4a (NESS 0327) (Ruiu, S.; Pinna, G. A.; Marchese, G.; Mussinu, J. M.; Saba, P.; Tambaro, S.; Casti, P.; Vargiu, R.; Pani, L. Synthesis and Characterization of NESS 0327: A Novel Putative Antagonist of CB1 Cannabinoid Receptor. J. Pharmacol. Exp. Ther. 2003, 306, 363-370) was synthesized and evaluated for their affinity to cannabinoid receptors. Depending on the chemical modification of the lead structure that was chosen, compounds 4b, 4c, 4i, 4l, and 4m still proved to be potent binders of the CB1 receptor. Moreover, several analogues (4c, 4d, 4e, and 4m) demonstrated superior CB2 receptor binding affinities compared to the parent ligand. Compounds 4b, 4c, 4i, and 4l displayed the most promising pharmacological profiles, having the highest selectivity for CB1 receptors with Ki(CB2) to Ki(CB1) ratios of 11 250, 2000, 3330 and 4625, respectively. Compound 4c increased the intestinal propulsion in mice and antagonized the effect induced by the CB1 receptor agonist WIN 55,212-2. Finally, molecular modeling studies were carried out on a set of tricyclic pyrazoles (2a-4a) and on rimonabant 1 (SR141716A), indicating that high CB1 receptors affinities were consistent for the tricyclic derivatives, both with a nonplanar geometry of the tricyclic cores and with a precise orientation of the substituent (chlorine) on this ring system
Blockade of neurotensin receptors affects differently hypo-locomotion and catalepsy induced by haloperidol in mice
No full textAntipsychotic drug treatment increases neurotensin (NT) neurotransmission, and the exogenous administration of NT produces antipsychotic-like effects in rodents. In order to investigate whether "endogenous" NT may act as a natural occurring antipsychotic or may mediate antipsychotic drug activity, the effects of the selective NT receptor antagonists SR 48692 and SR 142948A were analyzed in different behavioural tests of locomotor activity using vehicle, amphetamine, or haloperidol in mice. SR 48692 (0.1-1 mg/kg, i.p.) and SR 142948A (0.03-0.1 mg/kg, i.p.) failed to affect mouse spontaneous locomotor activity and amphetamine-induced (2.5 mg/kg, i.p.) hyper-locomotion. However, SR 48692 (0.1 and 0.3 mg/kg, i.p.) and SR 142948A (0.03 and 0.05 mg/kg, i.p.) significantly alleviated the reduction of locomotor activity elicited by haloperidol (0.01 and 0.04 mg/kg, s.c.) in vehicle- or amphetamine-treated mice. Finally, SR 48692 (0.3 mg/kg, i.p.) and SR 142948A (0.05 and 0.1 mg/kg, i.p.) increased mouse catalepsy produced by haloperidol (0.3 mg/kg, s.c.). The present results indicate that while endogenous NT is not involved in the modulation of either mouse spontaneous locomotor activity or amphetamine-induced hyper-locomotion, it might act by enhancing the therapeutic effects of haloperidol and by attenuating the extrapyramidal side effects elicited by this antipsychotic. © 2004 Elsevier Ltd. All rights reserved
The 5-HT2 antagonist ritanserin blocks dopamine re-uptake in the rat frontal cortex
No full textThe effect of ritanserin on dopamine (DA) re-uptake and efflux was studied in rat frontal cortex synaptosomes. When compared to other 5HT2 receptor antagonists such as ketanserin and risperidone or BA D2 receptor antagonists such as haloperidel and raclopride, the effect of ritanserin proved to be more potent. Ritanserin blocked the DA transporter with e K1 of 0.18 ± 0.06 μM, similar to cocaine (0.11 ± 0.005 μM), while ketanserin had a K1 of 0.93 ± 0.045; haloperidol of 2.07 ± 0.12; risperidone of 18.01 ± 0.62 and raclopride of 24.01 ± 1.55. In addition, 15 min from its local application to the synaptosomes, ritanserin potently released [3]H-DA leaving only 29.6 ± 1.6% of DA content, while ketanserin effect was equal to 45.5 ± 0.9%; haloperidol to 70.4 ± 2.2% and risperidone to 73.9 ± 1.5%, all tested at the dose of 10 μM. Cocaine had no effect on DA efflux. These results suggest that ritanserin has a intrinsic dopaminergic effect which may help to explain its reported improvement on mood, cognition and negative symptoms of schizophrenia
[3H]1-methyl-4-phenyl-2,3-dihydropyridinium ion binding sites in mouse brain: pharmacological and biological characterization
No full text
Effects of controlled-release formulations of atypical antipsychotics on functioning and quality of life of schizophrenic individuals.
No full textINTRODUCTION: Controlled-release formulations of atypical antipsychotics have
recently been introduced into clinical practice. Clinical studies have indicated
that these new therapies induce meaningful improvements in the functioning and
quality of life of schizophrenic individuals. AREAS COVERED: The present analysis
makes an attempt to address the clinical relevance of these studies and their
contribution to the understanding of the mechanisms of action of these new drugs.
A Medline search was done using the keywords 'antipsychotic', 'plasma level',
'quality of life' and 'functioning'. EXPERT OPINION: After reviewing the
literature, it seems that symptom control and side effects may play a role in
modulating the functioning and quality of life of schizophrenic individuals
treated with controlled-release formulations of atypical antipsychotics. The
analysis also highlights that these new drugs may possess peculiarities and
similarities in regulating patient functioning. However, the low number of
clinical analyses that have focused on these aspects of antipsychotic therapy
limits the interpretation of the results. Additional comparative clinical trials
are needed to evaluate how the pharmacokinetic/pharmacodynamic properties of
antipsychotic drugs may modulate the functioning and quality of life of
schizophrenic individuals, as well as to establish whether new clinical benefits
may come from the use of these drugs in schizophrenia therapy
Selected pyrethroid insecticides stimulate glutamate uptake in brain synaptic vesicles
No full textWe aimed to ascertain whether pyrethroid insecticides could influence the vesicular transport of the excitatory amino acid glutamate. The incubation of rat cortical synaptic vesicles with resmethrin and permethrin, consistently stimulated both ATP-dependent and -independent uptake of [3H]glutamate, while not evoking depletion of its vesicular content. Both processes were counteracted by valinomycin, a dissipator of the transmembrane potential gradient (deltapsi(sv)). Meanwhile, the vesicular influx of 36Cl- anions was impaired by pyrethroid concentrations which did not affect the ATP-dependent uptake of [14C]methylamine, as a marker for the proton gradient (deltapH). Thus, the stimulation of glutamate transport appeared to involve mainly the deltapsi(sv). A self-attenuating effect of selected pyrethroids on putatively enhanced excitatory transmission in severe intoxication is suggested
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