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1.
Residues of the second extracellular loop are believed to be important for ligand recognition in adenosine receptors. Molecular modeling studies have suggested that one such residue, Gln167 of the human A3 receptor, is in proximity to the C2 moiety of some adenosine analogs when bound. Here this putative interaction was systematically explored using a neoceptor strategy, i.e., by site-directed mutagenesis and examination of the affinities of nucleosides modified to have complementary functionality. Gln167 was mutated to Ala, Glu, and Arg, while the 2-position of several adenosine analogs was substituted with amine or carboxylic acid groups. All compounds tested lost affinity to the mutant receptors in comparison to the wild type. However, comparing affinities among the mutant receptors, several compounds bearing charge at the 2-position demonstrated preferential affinity for the mutant receptor bearing a residue of complementary charge. 13, with a positively-charged C2 moiety, displayed an 8.5-fold increase in affinity at the Q167E mutant receptor versus the Q167R mutant receptor Preferential affinity for specific mutant receptors was also observed for 8 and 12. The data suggests that a direct contact is made between the C2 substituent of some charged ligands and the mutant receptor bearing the opposite charge at position 167. 相似文献
2.
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
3.
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
4.
Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines 总被引:45,自引:0,他引:45
Adenosine has a significant role in many functions of the central nervous system. Behaviorally, adenosine and adenosine analogs have marked depressant effects. Electrophysiologically, adenosine reduces spontaneous neuronal activity and inhibits transsynaptic potentials interaction with extracellular receptors. Biochemically, adenosine inhibits adenylate cyclase a “high” affinity receptor, and activates adenylate cyclase a “low” affinity receptor. These receptors, called “A1” and “A2” respectively, show differing profiles for activation by adenosine analogs. Radioactive N6-cyclohexyladenosine binds selectively to the “high” affinity receptor. One major class of antagonists is known at adenosine receptors: the alkylxanthines, including caffeine and theophylline. Radioactive 1,3-diethyl-8-phenylxanthine, a particularly potent antagonist, appears to bind to both low and high affinity adenosine receptors. Behavioral, electrophysiological, and biochemical effects of alkylxanthines are consistent with the hypothesis that the central stimulatory actions of caffeine and theophylline are due in large part to antagonism of central adenosine receptors. 相似文献
5.
Serge Van Calenbergh Adriaan P. IJzerman Piet Herdewijn 《Nucleosides, nucleotides & nucleic acids》2013,32(9-11):1571-1576
Abstract Full adenosine A1 receptor agonists like CPA and other N 6-?substituted adenosine analogs have previously been shown to become partial agonists upon deletion of the 3′-hydroxyl moiety. The present study further explored the C-3′ site for modification. The modest affinity at A1 and A2a receptors found in the 3′-amido-3′-deoxyxyIofuranosyladenine series prompted us to synthesize the corresponding N 6-?cyclopentyl derivatives, which proved to exhibit potent antagonistic behaviour at the A1 receptors. This represents a new perspective in the purinergic field. 相似文献
6.
Catia Lambertucci Sauro Vittori Ram Chandra Mishra Diego Dal Ben Karl-Norbert Klotz Rosaria Volpini 《Nucleosides, nucleotides & nucleic acids》2013,32(10-12):1443-1446
The discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D 2 receptor activity by A 2 A adenosine receptor, potent and selective ligands of A 2 A subtype could be useful tools to study neurodegenerative disorders. A series of 2,8-disubstituted-9-ethyladenine derivatives was synthesized and tested in binding affinity assay at human adenosine receptors. New compounds showed good affinity and selectivity at A 2 A receptor versus the other subtypes. The introduction of a bromine atom in 8-position increased the affinity of these compounds, leading to ligands with K i in the nanomolar range. 相似文献
7.
《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
8.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):809-812
Abstract Adenosine derivatives bearing in 2-position the (R,S)- phenylhydroxypropynyl chain were evaluated for their potency at human A2B adenosine receptor, stably transfected on CHO cells, on the basis that (R,S)-2-phenylhydroxy-propynyl-5′-N-ethylcarboxyamidoadenosine [(R,S)-PHPNECA] was found to be a good agonist at the A2B receptor subtype. Biological studies demonstrated that the presence of small alkyl groups in N 6-position of these molecules are well tolerated, whereas large groups abolished A2B potency. On the other hand, the presence of an ethyl group in the 4′-carboxamido function seems to be optimal, the (S)-PHPNECA resulting the most potent agonist at A2B receptor reported so far. 相似文献
9.
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
10.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):927-930
Abstract Synthesis of 2′-deoxy-2′-fluoro-N 6-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A3 adenosine receptor are described. 相似文献
11.
Ranju Bansal Gulshan Kumar Deepika Gandhi Louise C. Young Alan L. Harvey 《化学与生物多样性》2011,8(7):1290-1300
A new series of 1H‐imidazol‐1‐yl substituted 8‐phenylxanthine analogs has been synthesized to study the effects of the imidazole group on the binding affinity of compounds for adenosine receptors. Competition binding studies of these compounds were carried out in vitro with human cloned receptors using [3H]DPCPX and [3H]ZM 241385 as radioligands at A1 and A2A adenosine receptors, respectively. The effect of the substitution pattern of the (imidazolyl)alkoxy group on various positions of the phenyl ring at C(8) was also studied. The xanthine derivatives displayed varying degrees of affinity and selectivity towards A1 and A2A receptor subtypes despite a common but variedly substituted Ar C(8). 相似文献
12.
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
13.
2- and 8-alkynyl-9-ethyladenines: Synthesis and biological activity at human and rat adenosine receptors 总被引:1,自引:1,他引:0
Volpini R Costanzi S Lambertucci C Vittori S Martini C Trincavelli ML Klotz KN Cristalli G 《Purinergic signalling》2005,1(2):173-181
The synthesis of a series of 9-ethyladenine derivatives bearing alkynyl chains in 2- or 8-position was undertaken, based on the observation that replacement of the sugar moiety in adenosine derivatives with alkyl groups led to adenosine receptor antagonists. All the synthesized compounds were tested for their affinity at human and rat A1, A2A, and A3 adenosine receptors in binding assays; the activity at the human A2B receptor was determined in adenylyl cyclase experiments. Biological data showed that the 2-alkynyl derivatives possess good affinity and are slightly selective for the human A2A receptor. The same compounds tested on the rat A1 and A2A subtypes showed in general lower affinity for both receptors. On the other hand, the affinity of the 8-alkynyl derivatives at the human A1, A2A, and A2B receptors proved to be lower than that of the corresponding 2-alkynyl derivatives. On the contrary, the affinity of the same compounds for the human A3 receptor was improved, resulting in A3 selectivity. As in the case of the 2-alkynyl-substituted compounds, the 8-alkynyl derivatives showed decreased affinity for rat receptors. However, it is worthwhile to note that the 8-phenylethynyl-9-ethyladenine was the most active compound of the two series (Ki in the nanomolar range) at both the human and rat A3 subtype. Docking experiments of the 2- and 8-phenylethynyl-9-ethyladenines, at a rhodopsin-based homology model, gave a rational explanation of the preference of the human A3 receptor for the 8-substituted compound. 相似文献
14.
A small library of peptidyl adenosine antibiotic analogs was synthesized, under the Pilot Scale Library Program of the NIH Roadmap initiative, from 2′,3′-O-isoproylideneadenosine-5′-carboxylic acid 2 in excellent yield. The coupling of the amino terminus of L-2-aminophenylbutyric methyl ester to a free 5′-carboxylic acid moiety of 2 followed by sodium hydroxide treatment led to carboxylic acid analog 4. Hydrolysis of this latter gave unprotected nucleoside analog 5. Intermediate 4 served as the precursor for the preparation of novel peptidyl adenosine analogs 6–18 in good yields and high purity through peptide coupling reactions to diverse amine derivatives. No marked anticancer and antimalaria activity was noted on preliminary cellular testing; however these analogs should be useful candidates for other types of biological activity. 相似文献
15.
Emilia Lubecka 《Biophysical chemistry》2010,151(3):139-148
In this paper, we use NMR spectroscopy and molecular modeling to examine four new vasopressin analogs modified with α-2-indanylglycine (Igl) at position 2, [L-Igl2]AVP (I), [D-Igl2]AVP (II), [Mpa1,L-Igl2]AVP (III) and [Mpa1,D-Igl2]AVP (IV), embedded in a sodium dodecyl sulfate (SDS) micelle. All the analogs display antiuterotonic activity. In addition, the analogs with D-Igl reveal antipressor properties.Each analog exhibits the tendency to adopt β-turns at positions 2, 3 and/or 3, 4, which is characteristic of oxytocin-like peptides. Mutual arrangement of aromatic residues at positions 2 and 3 has been found to be crucial for binding antagonists with the OT and V1a receptors. The orientation of the Gln4 side chain seems to be important for the V1a receptor affinity. In each of the peptides studied, the Gln4 side chain is folded back over the ring moiety. However, it lies on the opposite face of the tocin moiety in analogs with L and D enantiomers of Igl. 相似文献
16.
Michael E. Perlman 《Nucleosides, nucleotides & nucleic acids》2013,32(1):73-82
Abstract The 2′-deuterio arabino analogs of tubercidin and adenosine have been prepared by Swern oxidation of the 3′,5′-TPDS derivatives of tubercidin and adenosine and reduction with NaBD4. Subsequent inversion of stereochemistry at C-2′ yielded [2′-2H]tubercidin and [2′-2H]adenosine with 98% deuterium incorporation. 相似文献
17.
A. Garritsen M. W. Beukers A. P. Ijzerman W. Soudijn 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1107-1111
Abstract Amiloride and its analogues displace the adenosine A, receptor ligands [3H]CPDPX and [3H]PIA from their binding sites in calf brain membranes in a GTP-insensitive manner. High [NaCl] or low pH reduces the affinity of amiloride for A, receptors, whereas the affinity of [3H]CPDPX is not affected. Notwithstanding this difference in modulation, the interaction between amiloride and A, receptors appears competitive in nature. The structure-affinity relationships differ from those for classic amiloride-sensitive Na' transport systems, indicating that a coupling between the A, receptor and one of these systems is very unlikely. Amiloride and its analogues may reprcsent a novel class of A, receptor antagonists. 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.
Suhaib M. Siddiqi Xiao-duo Ji Neli Melman Mark E. Olah Rahul Jain Patricia Evans 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):693-717
Abstract The binding affinities at rat A1, A2a, and A3 adenosine receptors of a wide range of heterocyclic derivatives have been determined. Mono-, bi-, tricyclic and macrocyclic compounds were screened in binding assays, using either [3H]PIA or [3H]CGS 21680 in rat brain membranes or [125I]AB-MECA in CHO cells stably transfected with rat A3 receptors. Several new classes of adenosine antagonists (e. g. 5- oxoimidazopyrimidines and a pyrazoloquinazoline) were identified. Various sulfonylpiperazines, 11- hydroxytetrahydrocarbazolenine, 4H-pyrido[1,2-a]pyrimidin-one, folic acid, and cytochalasin H and J bound to A3 receptors selectively. Moreover, cytochalasin A, which bound to A1 adenosine receptors with Ki value of 1.9 μM, inhibited adenylyl cyclase in rat adipocytes, but not via reversible A1 receptor binding. 相似文献
20.
Ralf Schmidt Daniel Menard Carmen Mrestani-Klaus Nga N Chung Carole Lemieux Peter W Schiller 《Peptides》1997,18(10):1615-1621
Schmidt, R., D. Menard, C. Mrestani-Klaus, N. N. Chung, C. Lemieux and P. W. Schiller. Structural modifications of the N-terminal tetrapeptide segment of [d-Ala2]deltorphin I: effects on opioid receptor affinities and activities in vitro and on antinociceptive potency. Peptides 18(10) 1615–1621, 1997.—A series of deltorphin I analogs containing d- or l-N-methylalanine (MeAla), d- or l-proline (Pro), α-aminoisobutyric acid (Aib), sarcosine (Sar) or D-tert-leucine (Tle) in place of d-Ala2, or phenylalanine in place of Tyr1, was synthesized. The opioid activity profiles of these peptides were determined in μ and δ opioid receptor-representative binding assays and bioassays in vitro as well as in the rat tail flick test in vivo. In comparison with the deltorphin I parent, both the l- and the d-MeAla2-analog were slightly more potent δ agonists in the mouse vas deferens (MDV) assay, and the d-MeAla2-analog showed two-fold higher antinociceptive potency in the analgesic test. In view of the fact that deltorphin analogs with an unsubstituted l-amino acid residue in the 2-position generally lack opioid activity, the observed high δ opioid potency of [l-MeAla2]deltorphin I is postulated to be due to the demonstrated presence of a conformer with a cis Tyr1-MeAla2 peptide bond, since the cis conformer allows for a spatial arrangement of the pharmacophoric moieties in the N-terminal tripeptide segment similar to that in active deltorphin analogs containing a d-amino acid residue in the 2-position. Substitution of Aib in the 2-position led to a compound, H-Tyr-Aib-Phe-Asp-Val-Val-Gly-NH2, which displayed lower δ receptor affinity than the parent peptide but higher δ selectivity and, surprisingly, three times higher antinociceptive potency. The d- and l- Pro2-, Sar2- and d-Tle2-analogs showed much reduced δ receptor affinities and were inactive in the tail flick test. Replacement of Tyr1 in deltorphin I with Phe produced a 32-fold decrease in δ receptor affinity but only a 7-fold drop in antinociceptive potency. 相似文献