Adenosine A3 receptors: novel ligands and paradoxical effects

Jacobson, Kenneth A.

doi:10.1016/s0165-6147(98)01203-6

Cited by 287 publications

(277 citation statements)

References 42 publications

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“…This approach could be applied to the development of cardioprotective, cerebroprotective, and antiinflammatory agents acting through A 1 and A 3 receptors. 24 …”

Section: Discussionmentioning

confidence: 99%

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A 1 and A 3 receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A 1 , A 2A , and A 3 receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A 3 receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N 6 -substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A 1 or A 3 receptors, respectively, were synthesized. The N 6 -cyclopentyl derivatives were A 1 receptor-selective and maintained high efficacy at recombinant human but not rat brain A 1 receptors, as indicated by stimulation of binding of [ 35 S]GTP-γ-S. The (N)-methanocarba-N 6 -(3-iodobenzyl)adenosine and its 2-chloro derivative had K i values of 4.1 and 2.2 nM at A 3 receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A 3 receptors (EC 50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y 1 receptors, at least three adenosine receptors favor the ribose (N)-conformation.In work designed to develop potent and selective agents, the structure-activity relationships of adenosine derivatives as ligands (principally agonists) at the four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been explored extensively. Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).* Address correspondence to Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: (301) In general, for adenosine agonists, numerous modifications of the N 6 -position with cycloalkyl and other hydrophobic moieties provide selectivity for A 1 receptors, although the affinities of these N 6 -substituted adenosine derivatives (e.g. N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists. An intact f...

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“…This approach could be applied to the development of cardioprotective, cerebroprotective, and antiinflammatory agents acting through A 1 and A 3 receptors. 24 …”

Section: Discussionmentioning

confidence: 99%

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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“…The expression of A 3 receptors in the brain is lower than that of other adenosine receptor subtypes [6], and the affinity for adenosine, calculated from binding experiments in rat brain membranes (6.5 μM [2]), is lower than that of A 1 [7] and A 2A [8] receptors. However, during ischemic conditions in vivo [9] and in vitro [10] adenosine extracellular concentrations may be sufficiently high to activate adenosine A 3 receptors, which may play a role in brain ischemia (see [11,12]). …”

Section: Introductionmentioning

confidence: 99%

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Pugliese

Coppi

Volpini

et al. 2007

Biochemical Pharmacology

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The role of adenosine A 3 receptors in synaptic transmission under severe (7 min) and shorter (2-5 min) ischemic conditions, obtained by oxygen and glucose deprivation (OGD), was investigated in rat hippocampal slices. The effects of selective A 3 agonists or antagonists were examined on field excitatory postsynaptic potentials (fEPSPs) extracellularly recorded at the dendritic level of the CA1 pyramidal region. The novel, selective A 3 antagonist LJ1251 ((2R,3R,4S)-2-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol, 0.1-10 nM) protected hippocampal slices from irreversible fEPSP depression induced by severe OGD and prevented or delayed the appearance of anoxic depolarization. Similar results were obtained when severe OGD was carried out with a long, receptor-desensitizing exposure to various selective A 3 agonists: 5′-Nmethylcarboxamidoadenosine derivatives Cl-IB-MECA (N 6 -(3-iodobenzyl)-2-chloro), VT72 (N 6 -methoxy-2-phenylethynyl), VT158 (N 6 -methoxy-2-phenylethynyl), VT160 (N 6 -methoxy-2-(2-pyridinyl)-ethynyl), and VT163 (N 6 -methoxy-2-p-acetylphenylethynyl) and AR132 (N 6 -methyl-2-phenylethynyladenosine).The selective A 3 antagonist MRS1523 (3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine carboxylate, 100 nM) reduced fEPSP depression evoked by 2-min OGD and induced a faster recovery of fEPSP amplitude after 5-min OGD. Similar results were obtained for 2-or 5-min OGD applied in the presence of each of the A 3 agonists tested. Shorter exposure to A 3 agonists significantly delayed the recovery of fEPSP amplitude after 5-min OGD.This indicates that A 3 receptors, stimulated by selective A 3 agonists, undergo desensitization during OGD. It is inferred that CA1 hippocampal A 3 receptors stimulated by adenosine released during brief ischemia (2 and 5 min) might exert A 1 -like protective effects on neurotransmission. Severe ischemia would transform the A 3 receptor-mediated effects from protective to injurious.

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“…The reaction was stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with dichloromethane, washed with water, brine, and dried over MgSO 4 . Column chromatography (hexanes/ethyl acetate = 5/1) gave 0.588 g of light yellowish oil, yield = 15%.…”

Section: Preparation Of Methoxymethyl 4-(bromomethyl)-benzoate (31d) mentioning

confidence: 99%

Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A₃ Adenosine Receptors

Chang

et al. 1999

Bioconjugate Chem.

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Abstract4-Phenylethynyl-6-phenyl-1,4-dihydropyridine derivatives are selective antagonists at human A 3 adenosine receptors, with K i values in a radioligand binding assay vs [ 125 I]AB-MECA [N 6 -(4-amino-3-iodobenzyl)-5′-N-methylcarbamoyl-adenosine] in the submicromolar range. In this study, functionalized congeners of 1,4-dihydropyridines were designed as chemically reactive adenosine A 3 antagonists, for the purpose of synthesizing molecular probes for this receptor subtype. Selectivity of the new analogues for cloned human A 3 adenosine receptors was determined in radioligand binding in comparison to binding at rat brain A 1 and A 2A receptors. Benzyl ester groups at the 3-and/or 5-positions and phenyl groups at the 2-and/or 6-positions were introduced as potential sites for chain attachment. Structure-activity analysis at A 3 adenosine receptors indicated that 3,5-dibenzyl esters, but not 2,6-diphenyl groups, are tolerated in binding. Ring substitution of the 5-benzyl ester with a 4-fluorosulfonyl group provided enhanced A 3 receptor affinity resulting in a K i value of 2.42 nM; however, a long-chain derivative containing terminal amine functionalization at the 4-position of the 5-benzyl ester showed only moderate affinity. This sulfonyl fluoride derivative appeared to bind irreversibly to the human A 3 receptor (1 h incubation at 100 nM resulting in the loss of 56% of the specific radioligand binding sites), while the binding of other potent dihydropyridines and other antagonists was generally reversible. At the 3-position of the dihydropyridine ring, an amine-functionalized chain attached at the 4-position of a benzyl ester provided higher A 3 receptor affinity than the corresponding 5-position isomer. This amine congener was also used as an intermediate in the synthesis of a biotin conjugate, which bound to A 3 receptors with a K i value of 0.60 μM.

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Adenosine A3 receptors: novel ligands and paradoxical effects

Cited by 287 publications

References 42 publications

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A₃ Adenosine Receptors

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Adenosine A3 receptors: novel ligands and paradoxical effects

Cited by 287 publications

References 42 publications

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A3 Adenosine Receptors

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Product

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Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A₃ Adenosine Receptors