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1.
Gloria Cristalli Mario Grifantini Sauro Vittori Walter Balduini Flaminio Cattabeni 《Nucleosides, nucleotides & nucleic acids》2013,32(5):625-639
Abstract Several deaza-analogues of adenosine and 2-chloro-adenosine have been examined for their adenosine receptor affinity. It was found that the relative contribution of the nitrogen atoms of the purine moiety to binding at A1 rat brain adenosine receptor, follows the order N7 > N3 > N1. The affinity of the adenosine analogues for the adenosine rat brain receptor was besides compared with their activity as inhibitors of platelet aggregation. A synthesis of 2-chloro-1-deazaadenosine by two alternative routes starting from 7-nitroimidazo[4,5-b]pyridine-4-oxide is also reported. 相似文献
2.
Autoradiographic Localization and Characterization of Adenosine Receptor Subtypes in Mammalian Brain
Michael F. Jarvis 《Nucleosides, nucleotides & nucleic acids》2013,32(5):993-1001
Abstract Quantitative receptor autoradiography studies have shown that adenosine A1 receptors are heterogeneously distributed in the rat brain with high concentrations found in the forebrain and cerebellum. In contrast, high affinity A2 receptors appear to be exclusively localized in the striatum. These observations are discussed in relation to the putative neuromodulatory role of the purine in central neurotransmission. 相似文献
3.
Adenosine binding sites on 108CC15 neuroblastoma × glioma hybrid cells and rat brain membranes were investigated using [3H]adenosine as labelled ligand. Both the hybrid cells and brain membranes were found to have a high affinity binding site, Kd 0.8 and 3 nM respectively. The same ligand was used to demonstrate two lower affinity binding sites on brain membranes, Kds 1.4 and 29.1 μM and a single low affinity site on the hybrid cells, Kd 2.6 μM. Structure activity studies of the low affinity binding site on hybrid cells showed this to be an ‘R’ adenosine receptor of the A2 subtype. It is concluded that [3H]adenosine can be used to demonstrate both high and low affinity binding sites and that 108CC15 hybrid cells provide a valuable system for studying adenosine receptors. 相似文献
4.
Adenosine A1 and A2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A1 and A2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A1 receptor with Ki values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A2A receptor. These substitution patterns led to enhanced adenosine A1 and A2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A1 and A2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders. 相似文献
5.
G. Cristalli M. Grifantini S. Vittori W. Balduini F. Cattabeni 《Nucleosides, nucleotides & nucleic acids》2013,32(1-2)
Abstract A variety of adenosine analogues have been recently evaluated in order Lo find more potent and selective agonists on adenosine receptors. The most potent adenosine analogues acting on A1 receptor, a high affinity receptor inhibitory to adenylate cyclase, are N6-substituted compounds. So 6-cyclohexyladenosine (CHA) and 6-L-phenylisopropyladenosine (L-PIA) are extremely potent agonists on A2 receptor, whereas they are relatively weak agonists on A receptor, a lower affinity receptor which is stirnulatory to cyclase, and they have no effect on the adenosine P site. 相似文献
6.
《Journal of receptor and signal transduction research》2013,33(1-6):231-244
AbstractThe characteristics of adenosine receptors and adenosine uptake sites in brain are presented. High affinity adenosine receptors of the A1 type bind [3H]cyclohexyladenosine ([3H]CHA) and [3 H]diethyl-phenyl-xanthine ([3H]DPX) with 10?9 potency while adenosine uptake sites are labeled 10?10 potency with [3 H]nitrobenzyl-thioinosine ([3H]NBI). NBI does not inhibit either [3H]CHA (agonist) or [3H]DPX (antagonist) binding to adenosine receptors in brain cortical membranes and conversely CHA and other adenosine receptor ligands are very poor inhibitors of [3H]NBI binding to adenosine uptake sites. A number of other differences between the receptor and uptake site are discussed which provide rather strong evidence that these two sites are quite distinct and that the labeled ligands used represent specific probes for each site. 相似文献
7.
M. Milavec-krizman H. Wagner A. Kralj J. P. Evenou F. Gadient 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1127-1129
Abstract All adenosine receptor agonists, regardless of their A1/A2 selectivity ratio, dose dependently reduced blood pressure (MAP) whereas their effects on heart rate (HR) and plasma renin activity (PRA) depended on their receptor subtype selectivity. Thus an adenosine receptor agonist with an optimal A1- and A2- receptor selectivity (no increase in HR and PRA) and which does not penetrate the brain, might be a useful antihypertensive drug. 相似文献
8.
Michael F. Jarvis Michael Williams Un Hoi Do Matthew A. Sills 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1201-1202
Abstract The use of xanthine adenosine receptor antagonists such as 1,3-dipropyl-8-phenylxanthine (DPX) as radioligands for the characterization of adenosine receptor Pharmacology have been limited by their high lipophilicity, low specific activity, and their general lack of selectivity and affinity for adenosine receptors. Recent attempts to address the technical problems associated with this class of compounds has resulted in the development of several xanthine derivatives (e.g. the functionalized xanthine congeners [3H]XCC and [3H]XAC2, and [3H]CPX3) which bind with high and selective affinity to the adenosine A1 receptor subtype. Based on efforts to optimize non-xanthine adenosine receptor antagonists, CGS 15943, a derivative of the pyrazoloquinazoline benzodiazepine receptor inverse agonist CGS 82165, represents the first reported non-xanthine structure that potently blocks adenosine receptors6. CGS 15943 has nanomolar affinity for both A1 and A2 receptor subtypes6. However, in contrast to many of the xanthine adenosine receptor antagonists, CGS 15943 is not a phosphodiesterase inhibitor and does not interact with adenosine transporter sites6. This compound is a potent and selective adenosine receptor antagonist in vivo 7 with a solubility/affinity ratio of greater than 10007. In the present studies, the binding of [3H]CGS 15943 to the adenosine A1 receptor was characterized. 相似文献
9.
《Journal of receptor and signal transduction research》2013,33(7-8):905-929
AbstractThe binding characteristics of radiolabeled N6-(cyclohexyl)adenosine ([3H]CHA), N6-(R-phenylisopropyl)adenosine ([3H]R-PIA), 5′-N-ethylcarboxamidoadenosine ([3H]NECA), and 2-[4-(2-carboxyethyl)phenyl]ethyl-amino-5′-N-ethylcarboxamidoadenosine ([3H]CGS 21680), to rat testis membranes were investigated. Specific binding of [3H]CGS 21680, a selective agonist for the A2a adenosine receptor, was very modest whilst the nonselective agonist [3H]NECA bound to rat testis membranes showing high binding capacity. At least two types of binding sites for [3H]NECA could be identified in rat testis membranes: high affinity sites and high capacity sites. Selective agonists for the At adenosine receptor, [3H]CHA and [3H]R-PIA bound with high affinity to a single class of binding sites. This high affinity binding site showed the typical pharmacological specificity of the A1 adenosine receptor with a potency order for agonists of CHA R-PIA > NECA > N6-(S-phenylisopropyl)adenosine (S-PIA). In order to detect the presence of the A3 adenosine receptor in these membranes we selectively blocked the A1 receptor with a large molar excess of a xanthine antagonist, either 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or xanthine amine congener (XAC). In the presence of an antagonist a low affinity binding site for [3H]CHA and [3H]R-PIA was detected. This low affinity binding site showed a different pharmacological specificity than the high affinity binding site. In fact the potency order for agonists was CHA NECA = R-PIA > S-PIA. This finding suggests that the low affinity binding site represents the A3 adenosine receptor. 相似文献
10.
Abstract Studies on the pH dependence of ligand binding to A1 adenosine receptors revealed that protonation of a histidine residue in the binding pocket is accompanied by high affinity agonist binding. 相似文献
11.
Roslyn Lefin Mietha M. van der Walt Pieter J. Milne Gisella TerreBlanche 《Bioorganic & medicinal chemistry letters》2017,27(17):3963-3967
Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A1 receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A1 and A2A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A1 receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A1 and A2A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A1 or A2A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A1 or A2A receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A1 receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A1 receptor with a Ki value of 2.06 µM and (2) adenosine A1 receptor antagonistic properties. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenyl-imidazo[1,2-α]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-α]pyridine-based adenosine A1 receptor antagonists for the treatment of neurodegenerative disorders. 相似文献
12.
Romain Duroux Nicolas Renault Joana Esteves Cuelho Laurence Agouridas David Blum Luisa V. Lopes 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):850-864
The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1?μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184?μm) without being cytotoxic at 100?μm. This compound, along with low-molecular weight compound D1 (Ki?=?10?μm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation. 相似文献
13.
Abstract The syntheses of three classes of adenosine analogues involving cyclosubstitution at the 6-position and functionalization at the 2-position are reported. The target molecules synthesized are stable with respect to hydrolytic deamination by mammalian adenosine deaminase, and, because of major structural changes at the 2- and 6-positions, these compounds are expected to be poor phosphorylation substrates for the kinases. Adenosine receptor binding data reveal that several of the compounds synthesized show excellent A1 receptor affinity and A2/A1 selectivity. 相似文献
14.
Moon Woo Chun Sung Wook Choi Tae Kyung Kang Won Jun Choi Hea Ok Kim Zhan-Guo Gao 《Nucleosides, nucleotides & nucleic acids》2013,32(4):408-420
On the basis of high binding affinity of 3′-aminoadenosine derivatives 2b at the human A3 adenosine receptor (AR), 3′-acetamidoadenosine derivatives 3a–e were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose via stereoselective hydroboration as a key step. Although all synthesized compounds were totally devoid of binding affinity at the human A3AR, our results revealed that 3′-position of adenosine can only be tolerated with small size of a hydrogen bonding donor like hydroxyl or amino group in the binding site of human A3AR. 相似文献
15.
The kinetics and sodium dependence of adenosine transport were determined using an inhibitorstop method on dissociated cell body preparations obtained from mouse guinea-pig and rat brain. Transport affinity (KT) values for the high affinity adenosine transport systems (KT(H)) were significantly different between these three species; mean ±SEM values were 0.34 ±0.1 in mouse, 0.9 ±0.2 in rat, and 1.5±0.5 M in guinea-pig. The KT values for the low affinity transport system (KT(L)) were not different between the three species. Brain cells from rat displayed a significantly greater maximal capacity to accumulate [3H]adenosine (Vmax) than did mouse or guinea-pig for the high affinity system, or than did mouse for the low affinity system. When sodium chloride was replaced in the transport medium with choline chloride, the KT(H) values for guinea-pig and rat were both increased by approximately 100%; only in rat did the change reach statistical significance. The sodium-dependence of adenosine transport in mouse brain was clearly absent. The differences between KT(H) values in mouse and those in guinea-pig or rat were accentuated in the absence of sodium. The differences in kinetic values, ionic requirements, and pharmacological characteristics between adenosine transporters in CNS tissues of mouse guinea-pig and rat may help account for some of the variability noted among species in terms of their physiological responses to adenosine. 相似文献
16.
S. Vittori E. Camaioni S. Costanzi R. Volpini K-N. Klotz G. Cristalli 《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):739-740
Abstract In a search for potent and selective adenosine agonists it has been found that 2-hexynyladenosine-5′-N-ethyluronamide (HENECA) displays high affinity at rat A2A receptor combined with a good A2A vs A1 selectivity. The finding that HENECA shows good affinity also for A3 receptors prompted us to investigate the effect of various substituents in different positions of this molecule. 相似文献
17.
A1 adenosine receptor of rat testis membranes. Purification and partial characterization 总被引:1,自引:0,他引:1
H Nakata 《The Journal of biological chemistry》1990,265(2):671-677
Purification of an A1 adenosine receptor of rat testes was performed using a newly developed affinity chromatography system (Nakata, H. (1989) Mol. Pharmacol. 35, 780-786). The A1 adenosine receptor was solubilized with digitonin from rat testicular membranes and then purified more than 25,000-fold by sequential use of affinity chromatography on xanthine amine congener-immobilized agarose, hydroxylapatite chromatography, re-affinity chromatography on xanthine amine congener-agarose, and finally gel permeation chromatography on TSK-3000SW. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the final preparation showed a single broad band of Mr 41,000 by autoradiography after radioiodination. This Mr 41,000 peptide was also specifically labeled with an A1 adenosine receptor affinity labeling reagent. A high affinity A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-[3H]dipropylxanthine, bound saturably to the purified receptor with a KD of approximately 1.4 nM. The purified receptor also showed essentially the same specificity for adenosine agonists and antagonists as the unpurified receptor preparations, although the affinities of the purified adenosine receptor for agonists were significantly low compared to those of unpurified receptor preparations indicating that the purified A1 adenosine receptor exists as a low agonist-high antagonist affinity state. Deglycosylation of the purified testis adenosine A1 receptors with endoglycosidase F produced an increase in the mobility of the receptor protein to an apparent Mr 30,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, similar to that of deglycosylated A1 adenosine receptors of rat brain membranes. Peptide maps of the purified testis and brain A1 adenosine receptors using trypsin and V8 protease suggest that these receptors show some structural homologies. 相似文献
18.
Philip J.M. van Galen Adriaan P. Ijzerman Willem Soudijn 《Nucleosides, nucleotides & nucleic acids》2013,32(2):275-291
Abstract The synthesis and A1 adenosine receptor affinity of some xanthine-7-ribosides is described. It appears that these compounds are A, receptor antagonists. The orientation of the ribose moiety, as determined by ′H-NMR spectroscopy and theoretical chemical calculations, is compared with the orientation of the ribose in the agonist adenosine. Implications for the syn vs anti modes of binding to the receptor are discussed. 相似文献
19.
《Nucleosides, nucleotides & nucleic acids》2013,32(4-7):343-360
Compound 20 (CVT-3146 - a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and compound 31 (CVT-3033 - a 2-[(4-(1-N-pentyl-pyrazolyl)] adenosine derivative), were found to be short acting functionally selective coronary vasodilators (CV t0.5 = 5.2 ± 0.2 and 3.4 ± 0.5 min, respectively - rat isolated heart 50% reversal time) with good potency (EC50s = 6.4 ± 1.2 nM and 67.9 ± 16.7 nM, respectively), but they possess low affinity for the ADO A2A receptor (Ki = 1122 ± 323 nM and 2138 ± 952 nM, respectively; pig striatum). 相似文献
20.
J. C. Oliveira A. M. Sebastião J. A. Ribeiro 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1135-1137
Abstract The use of [3H]-L-phenylisopropyladenosine ([3H]-L-PIA) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) in binding assays to solubilized preparations from rat brain membranes suggested the presence of an A1, and a non-A1 non-A2 adenosine receptor may be equivalent to the A3 subtype. 相似文献