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Adenosine Receptor Antagonist (adenosine + receptor_antagonist)
Selected AbstractsSynthesis and Structure,Activity Relationships of a New Set of 1,2,4-Triazolo[4,3-a]quinoxalin-1-one Derivatives (I) and (II) as Adenosine Receptor Antagonists.CHEMINFORM, Issue 46 2003Vittoria Colotta No abstract is available for this article. [source] Estimation of endogenous adenosine activity at adenosine receptors in guinea-pig ileum using a new pharmacological methodACTA PHYSIOLOGICA, Issue 2 2010K. F. Nilsson Abstract Aim:, Adenosine modulates neurotransmission and in the intestine adenosine is continuously released both from nerves and from smooth muscle. The main effect is modulation of contractile activity by inhibition of neurotransmitter release and by direct smooth muscle relaxation. Estimation of adenosine concentration at the receptors is difficult due to metabolic inactivation. We hypothesized that endogenous adenosine concentrations can be calculated by using adenosine receptor antagonist and agonist and dose ratio (DR) equations. Methods:, Plexus-containing guinea-pig ileum longitudinal smooth muscle preparations were made to contract intermittently by electrical field stimulation in organ baths. Schild plot regressions were constructed with 2-chloroadenosine (agonist) and 8-(p -sulfophenyl)theophylline (8-PST; antagonist). In separate experiments the reversing or enhancing effect of 8-PST and the inhibiting effect of 2-chloroadenosine (CADO) were analysed in the absence or presence of an adenosine uptake inhibitor (dilazep), and nucleoside overflow was measured by HPLC. Results:, Using the obtained DR, baseline adenosine concentration was calculated to 28 nm expressed as CADO activity, which increased dose dependently after addition of 10,6 m dilazep to 150 nm (P < 0.05). HPLC measurements yielded a lower fractional increment (80%) in adenosine during dilazep, than found in the pharmacological determination (440%). Conclusion:, Endogenous adenosine is an important modulator of intestinal neuro-effector activity, operating in the linear part of the dose,response curve. Other adenosine-like agonists might contribute to neuromodulation and the derived formulas can be used to calculate endogenous agonist activity, which is markedly affected by nucleoside uptake inhibition. The method described should be suitable for other endogenous signalling molecules in many biological systems. [source] Stabilizing effects of extracellular ATP on synaptic efficacy and plasticity in hippocampal pyramidal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2005Eduardo D. Martín Abstract The role of adenosine triphosphate (ATP) as a neurotransmitter and extracellular diffusible messenger has recently received considerable attention because of its possible participation in the regulation of synaptic plasticity. However, the possible contribution of extracellular ATP in maintaining and regulating synaptic efficacy during intracellular ATP depletion is understudied. We tested the effects of extracellular ATP on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by Schaffer collateral stimulation. In the absence of intracellular ATP, EPSC rundown was neutralized when a low concentration of ATP (1 µm) was added to the extracellular solution. Adenosine and ATP analogues did not prevent the EPSC rundown. The P2 antagonists piridoxal-5,-phosphate-azophenyl 2,,4,-disulphonate (PPADS) and reactive blue-2, and the P1 adenosine receptor antagonist 8-cyclopentyltheophylline (CPT) had no detectable effects in cells depleted of ATP. However, the protective action of extracellular ATP on synaptic efficacy was blocked by extracellular application of the protein kinase inhibitors K252b and staurosporine. In contrast, K252b and staurosporine per se did not interfere with synaptic transmission in ATP loaded cells. Without intracellular ATP, bath-applied caffeine induced a transient (< 35 min) EPSC potentiation that was transformed into a persistent long-term potentiation (> 80 min) when 1 µm ATP was added extracellularly. An increased probability of transmitter release paralleled the long-term potentiation induced by caffeine, suggesting that it originated presynaptically. Therefore, we conclude that extracellular ATP may operate to maintain and regulate synaptic efficacy and plasticity in conditions of abnormal intracellular ATP depletion by phosphorylation of a surface protein substrate via activation of ecto-protein kinases. [source] Abstract no.: 2 The influence of clozapine on tone of isolated bovine retinal arteriesFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Koen Boussery Aims:, It has been suggested that the atypical antipsychotic drug clozapine might be helpful in the development of new antiglaucoma agents, since it combines lowering of the intra-ocular pressure after topical instillation with vasodilation. However, the vasoactive influence of clozapine on ocular blood vessels has never been analysed. Therefore, this study aimed to evaluate whether clozapine has direct vasodilatory effects in isolated bovine retinal arteries (BRA) and to characterise pharmacologically the mechanisms involved. Methods:, Retinal arteries were isolated from bovine eyes and mounted in a wire-myograph for isometric tension recording. Concentration-response curves were generated by cumulative addition of clozapine (1 nM to 10 ,M) to the organ bath. Results:, Clozapine elicited a concentration-dependent relaxation of the BRA. Removal of the endothelium of the BRA, inhibition of nitric oxide synthase with N, -nitro-L-arginine and inhibition of soluble guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly attenuated the clozapine-response, whereas cyclo-oxygenase inhibition with indomethacin had no influence. The Ca2+ channel activator Bay k8644, the nonselective 5-hydroxytryptamine receptor antagonist methiothepin and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline also failed in affecting the clozapine-induced relaxations. Conclusion:, Clozapine clearly relaxes bovine retinal arteries in a direct way. Endothelium-derived NO is involved in this response. However, prostanoids, calcium entry blockade, 5-HT7 receptor stimulation and adenosine receptor stimulation all seem to be not involved. [source] Influence of differently ionized species on fragmentation pathways and energetics of a potential adenosine receptor antagonist using a triple quadrupole and a multistage LTQ-OrbitrapÔ FTMS instrumentJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 4 2009Wendy Zhong A systematic study was conducted to investigate the influence of differently ionized species on the fragmentation pathways and energetics of a piperazine-containing adenosine by using different cations or anions. Very different fragmentation mechanisms were observed in protonated- versus sodiated-molecules, which indicated that the proton is mobilized to promote the charge-direct fragmentation, whereas Na+ cation was fixed at the heterotricyclic ring structure provoking charge-remote fragment ions. This finding was also supported by the results observed in the fragmentation behaviors in the deprotonated-molecule. The energetics of these fragment ions were also explored by using the breakdown curves obtained from the triple quadrupole and LTQ-OrbitrapÔ instrument. The data indicated that the lowest energy pathways in the protonated-molecule [M+H]+ involve breaking a CN bond connecting an ethylene bridge and heterotricyclic ring structure. The lowest energy pathway is the cleavage of a CO bond connecting the methoxy ethyl group and phenolic oxygen to form a distonic radical ion for a sodiated-molecule [M+Na+]and a deprotonated-molecule [M-H],. The data suggest that by choosing the differently ionized species, one can probe different fragmentation channels that can provide additional structure information for an unknown impurity and possibly degradation product identification. In addition, by comparing the data obtained from triple quadrupole and LTQ-Orbitrap instruments, one can develop further understanding of the differences in the fragmentation behaviors due to the variations in the collision activation-dissociation process. From the side-by-side comparison with the breakdown curves obtained for both instruments, the difference in fragmentation behaviors caused by the difference in dissociation processes that occur in these two types of instruments can be probed. J. Heterocyclic Chem., (2009). [source] Assessment and Characterization of Purinergic Contractions and Relaxations in the Rat Urinary BladderBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2010Patrik Aronsson ATP elicited a transient bladder contraction followed by a sustained relaxation and ADP, UDP and UTP generated predominantly potent relaxations (relaxatory potencies: ADP = ATP > UDP = UTP). The ATP contractions were desensitized with the P2X1/3 purinoceptor agonist/desensitizer ,,,-meATP and reduced by the P2 purinoceptor antagonist PPADS but unaffected by the P2 purinoceptor antagonist suramin. Electrical field stimulation (1,60 Hz) evoked frequency-dependent bladder contractions that were decreased by incubation with ,,,-meATP but not further decreased by PPADS. Suramin antagonized relaxations generated by UDP but not those by ADP, ATP or UTP. PPADS antagonized and tended to antagonize UTP and UDP relaxations, respectively, but did neither affect ADP nor ATP relaxations. ADP relaxations were insensitive to the P2Y1 purinoceptor antagonist MRS 2179 and the ATP-sensitive potassium channel antagonist glibenclamide. The ATP relaxations were inhibited by the P1 purinoceptor antagonist 8-p-sulfophenyltheophylline but unaffected by the A2A adenosine receptor antagonist 8-(3-chlorostyryl)caffeine and glibenclamide. Adenosine evoked relaxations that were antagonized by the A2B adenosine receptor antagonist PSB 1115. Thus, in the rat urinary bladder purinergic contractions are elicited predominantly by stimulation of the P2X1 purinoceptors, while UDP/UTP-sensitive P2Y purinoceptor(s) and P1 purinoceptors of the A2B adenosine receptor subtype are involved in bladder relaxation. [source] Bioisosterism, enantioselectivity, and molecular modeling of new effective N6 - and/or N(9)-substituted 2-phenyl adenines and 8-aza analogs: Different binding modes to A1 adenosine receptorsDRUG DEVELOPMENT RESEARCH, Issue 2 2001A. Maria Bianucci Abstract Bioisosterism of the adenine and 8-azaadenine nuclei was demonstrated by comparison of A1 adenosine receptor binding affinity of 2-phenyl N6 -substituted adenines and the corresponding 8-azaadenines. Some of these new compounds are very potent A1 adenosine receptor antagonists. This work also describes the synthesis and A1 adenosine receptor binding of the enantiomers of some 2-phenyladenines substituted with a 1-phenylethyl chiral group in N6 and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2-phenylsubstituted adenines inside A1 adenosine receptors. Theoretical studies, based on an improved A1 adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52,65, 2001. © 2001 Wiley-Liss, Inc. [source] Vascular effects of adenosine and its analoguesDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Debbie Prentice Abstract The main action of adenosine on vascular beds is vasodilation via A2 receptors. In addition, A1 receptors are found in some blood vessels, where they cause contraction. Traditionally, adenosine-induced vasodilation in vitro has been attributed to A2A receptor activation; however, it is now clear that A2B receptors are also involved in the regulation of vascular tone. Endothelium dependence of A2 receptor-mediated responses is variable; in some tissues they are blocked by removal of endothelium and/or inhibition of NO-synthase and in some they are not. In addition to A2 receptor-mediated relaxation, there is much evidence that relaxations to adenosine and some of its analogues can also be mediated by a mechanism which cannot be blocked by adenosine receptor antagonists. There is evidence that these responses are endothelium- and NO-independent and that, under conditions where adenosine is taken up into cells, relaxations to the endogenous ligand are entirely mediated by this mechanism, suggesting it is of physiological significance. Drug Dev. Res. 52:346,349, 2001. © 2001 Wiley-Liss, Inc. [source] Predictive 3D-Quantitative Structure-Activity Relationship for A1 and A2A Adenosine Receptor LigandsMOLECULAR INFORMATICS, Issue 11-12 2009Olga Yuzlenko Abstract The use of QSAR applications to develop adenosine receptor (AR) antagonists is not so common. A library of all xanthine derivatives, obtained at the Department of Technology and Biotechnology of Drugs, was created. Sixty-three active adenosine A1 receptor ligands and one hundred thirty nine active adenosine A2A receptor ligands were used for 3D-QSAR investigation. The 3D-QSAR equations with a high predictive power in estimating the binding affinity values of potential A1 and A2A ARs ligands were derived. For the first time, hybrid shape-property descriptors were used in 3D-QSAR for xanthine ARs ligands. The obtained models were characterized by a high regression and cross-validation coefficients. Two types of the model validation were tested , dividing the library into the training set for model development and external set for model validation and increasing the number of library components and checking the model by cross-validated regression coefficient. The analysis of the results depicts that for the A1 AR binding activity it is important for ligands to possess R1 -propyl substituents along with the phenyl or benzyl substituents bearing halogen atom and phenethyl moiety. For A2A AR affinity it could be favorable to introduce phenethyl or phenyl substituent connected with the tricyclic ring by the alkoxy chain. The nature of R1 group may not significantly affect the A2A AR affinity. High predictive power of the equations suggests their use for further development of adenosine receptor antagonists within xanthine derivatives. [source] Flavonoids as antagonists at A1 adenosine receptorsPHYTOTHERAPY RESEARCH, Issue 11 2006Stephen P. H. Alexander Abstract This study aimed to investigate the potential for ,avonoid action at A1 adenosine receptors in vitro. In a radioligand binding assay for A1 adenosine receptor occupancy in particulate preparations from guinea-pig cerebral cortex, flavonoids competed in concentration-dependent manners with Hill slopes typically not different from unity. Of the ,avonoids tested, quercetin showed highest affinity (pKi value of 5.33). At a concentration of 28 mm, quercetin evoked a rightward shift in the N6 -cyclopentyladenosine-induced inhibition of electrically evoked contractions of the guinea-pig isolated ileum, allowing the calculation of a pKi value of 4.71. These data suggest, therefore, that ,avonoids represent an additional dietary source of A1 adenosine receptor antagonists (beyond the methylxanthines, caffeine and theophylline). Copyright © 2006 John Wiley & Sons, Ltd. [source] | ||||||||||||||||