1,721,026 research outputs found
Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease
No full textPreclinical evidence strongly indicate that adenosine A(2A) receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A(2A) receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A(2A) antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A(2A) antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A(2A) antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A(2A) antagonists
Blockade of adenosine A2A receptors antagonizes parkinsonian tremor in the rat tacrine model by an action on specific striatal regions
No full textAcute administration of the acetylcholinesterase inhibitor tacrine to rats induces tremulous jaw movements which can be used as a valuable model of parkinsonian tremor. In the present study, the number of tremor episodes and jaw movements were evaluated to assess the effects of the selective A2A antagonists SCH 58261 and SCH BT2 on tremorgenesis. SCH 58261 dose-dependently, and maximally at 5 mg/kg, reduced the number of both tremor episodes (-35%) and jaw movements (-50%), induced in rats by tacrine (2.5 mg/kg ip). Since adenosine A2A receptors are largely expressed throughout the striatum, chronic cannulae were implanted in the rat dorsomedial (DMS) and ventrolateral striatum (VLS) to investigate whether A2A antagonists could act at this level. Infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, in VLS antagonized both tremor episodes (-68%) and jaw movements (-76%) elicited by tacrine (2.5 mg/kg ip), whereas SCH BT2 infusion in DMS was less effective in blocking jaw movements (-50%) and did not significantly affect the number of tremor episodes. Taken together, the results of this study indicate that A2A antagonists effectively reduce the magnitude of tremulous jaw movements induced in rats by acute tacrine, mainly by an action in VLS and suggest that A2A antagonists might be used as specific agents against parkinsonian tremor
Selective adenosine A2A receptor antagonists suppress jaw movements in the rat tacrine model of parkinsonian tremor
No full textBlockade of pallidal adenosine A2A receptors potentiates contralateral rotational behavior induced by L-DOPA and dopaminergic agonists in hemiparkinsonian rats
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Involvement of globus pallidus in the antiparkinsonian effects of adenosine A2A receptor antagonists
No full textAn involvement of globus pallidus (GP) in the antiparkinsonian effects of A(2A) receptor antagonists has been proposed on the basis of the selective localization of A(2A) receptors on the striatopallidal pathway. In order to investigate this possibility, the present study evaluated rotational behavior in unilaterally 6-hydroxydopamine-lesioned rats following infusion of the water-soluble A(2A) receptor antagonist SCH BT2 into GP. SCH BT2 (5 microg/1 microl) altered neither motor behavior nor produced postural asymmetry by itself. However, when infused concomitantly with a parenteral subthreshold dose of l-DOPA (3 mg/kg i.p.) capable of inducing modest contralateral rotational behavior (34.7 +/- 20.7/1 h), SCH BT2 significantly potentiated the number of contraversive rotations (167.4 +/- 16.3/1 h). These results suggest that A(2A) receptors located in the globus pallidus may be involved in the antiparkinsonian effects of A(2A) antagonists
SYNTHESIS AND CYTOTOXICITY OF DNA-INTERACTIVE PYRROLO[2,1-C][1,4]BENZODIAZEPINONE HETEROCYCLIC-ANALOGS
No full textThe pyrrolo[2,1-C][1,4]benzodizepines (PBDs) are a family of sequence-selective DNA-binding anti tumor antibiotics that bind exclusively to the exocyclic N2 of guanine in the minor groove of DNA. Footprinting-type studies have shown that the adduct span 3 base-pairs with a rank order of preference for 5'-Pu-G-Pu>5'->Pu-G-Py or 5'-Py-G-Pu>5'-Py-G-Py sequences. In a project aimed to design new analogues lacking both cardiotoxicity and tissue necrosis, we have substituted theA benzene ring of the PBD skeleton with different heterocycle nucleus such as substituted pyrazoles, pyridine and pyrimidine. The rationale behind the synthesis of the heterocyclic analogues reported here has been to design molecules with the following features:i)a possibly higher binding affinity and modified sequence selectivity for the DNAminor groove, due to the potential new hydrogen bonds that might occur between the A-ring atoms and DNA bases;ii)a reduced cardiotoxicity due to the impossibility of C9-quinone formation as occurs with anthramycin. The synthesized compounds were evaluated for cytotoxicity by growth inhibition studies in L1210 murine leukemia and its L1210/L-PAM sublime cells resistant to melphalan (L-PAM) and LoVo human coloncarcinoma and its sublime (LoVo/DX) resistant to Doxorubicin(DX). Among the most cytotoxic compounds containing the pyrazole ring it is interesting to note that:1)substitution at N7 increases cytotoxicity with respect to the N6 substituted compounds in L1210 and L1210/L-PAM cell lines;2)the N7 benzyl or N7 substituted benzyl compounds are similar or superior to N7 methyl or ethyl substituted compounds in terms of cytotoxicity; 3)with the same substituent at N6 replacement of the C8 methyl group with a carboxy methyl ester does not increase cytotoxicity.4)in the L1210 cell line, the introduction of a sterically demanding substituent at C8leads to a decrease in citotoxicity compared to the C8-methyl compound
Synthesis of 3-Substituted 7-Methyl-5H-pyrazole[4,3-d]-1,2,3-triazin- 4(3H)-ones and Amide-N-Substituted 3-Methyl-4-diazopyrazole-5-carboxamides
No full textDiazotization of amide-N-substituted 4-amino-3-methylpyrazole-5-carboxamides 4 with sodium nitrite and acetic acid produces 3-substituted 7-methyl-5H-pyrazolo[4,3-d]-1,2,3-triazin-4(3H)-ones 6 or amide-N-substituted 3-methyl-4-diazopyrazole-5-carboxamides 5, depending on the substitution pattern. © 1988 Georg Thieme Verlag. All rights reserved.Diazotization of amide-N-substituted 4-amino-3-methylpyrazole-5-carboxamides 4 with sodium nitrite and acetic acid produces 3-substituted 7-methyl-5H-pyrazolo[4,3-d]-1,2,3-triazin-4(3H)-ones 6 or amide-N-substituted 3-methyl-4-diazopyrazole-5-carboxamides 5, depending on the substitution pattern
Synthesis of 1H-pyrazolo[4,3-D]pyrimidine-7(6H)-ones and pyrazolo-5-carboxamides and interaction with benzodiazepine and adenosine-A1 receptors in rat cerebral-cortex
No full textThe effects of several newly synthesized pyrazolo [4,3-d] pyrimidine-7-ones and pyrazolo-5-carboxamides on [3H]-flunitrazepam and [3H]-cyclohexyladenosine binding in rat cerebral cortex membranes have been studied. The compounds under examination, displaying affinities in the micromolar range for both benzodiazepine and adenosine A1 receptors, could be of interest in the study of a possible link between the two receptor systems
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