N<sup>6</sup>-Substituted D-4‘-Thioadenosine-5‘-methyluronamides:  Potent and Selective Agonists at the Human A<sub>3</sub>Adenosine Receptor

Jeong, Lak Shin; Jin, Dong Zhe; Kim, Hea Ok; Shin, Dae Hong; Moon, Hyung Ryong; Gunaga, Prashantha; Chun, Moon Woo; Kim, Yong-Chul; Melman, Neli; Gao, Zhan‐Guo; Jacobson, Kenneth A.

doi:10.1021/jm034098e

Cited by 84 publications

(64 citation statements)

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“…Similar to previous studies of the N 6 -position [8] and the ribose moiety [9,30,31], structural determinants at the 2-position of adenosine have been found to be critical for A 3 AR recognition and activation. Fig.…”

Section: Discussionsupporting

confidence: 83%

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Gao

Mamedova

Chen

et al. 2004

Biochemical Pharmacology

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The affinity and efficacy at four subtypes (A 1 , A 2A , A 2B and A 3 ) of human adenosine receptors (ARs) of a wide range of 2-substituted adenosine derivatives were evaluated using radioligand binding assays and a cyclic AMP functional assay in intact CHO cells stably expressing these receptors. Similar to previous studies of the N 6 -position, several 2-substituents were found to be critical structural determinants for the A 3 AR activation. The following adenosine 2-ethers were moderately potent partial agonists (K i , nM): benzyl (117), 3-chlorobenzyl (72), 2-(3-chlorophenyl)ethyl (41), and 2-(2-naphthyl)ethyl (130). The following adenosine 2-ethers were A 3 AR antagonists: 2,2-diphenylethyl, 2-(2-norbornan)ethyl, R-and S-2-phenylbutyl, and 2-(2-chlorophenyl)ethyl. 2-(S-2-Phenylbutyloxy)a-denosine as an A 3 AR antagonist right-shifted the concentration-response curve for the inhibition by NECA of cyclic AMP accumulation with a K B value of 212 nM, which is similar to its binding affinity (K i = 175 nM). These 2-substituted adenosine derivatives were generally less potent at the A 1 AR in comparison to the A 3 AR, but fully efficacious, with binding K i values over 100 nM. The 2-phenylethyl moiety resulted in higher A 3 AR affinity (K i in nM) when linked to the 2-position of adenosine through an ether group (54), than when linked through an amine (310) or thioether (1960). 2-[2-(lNaphthyl)ethyloxy]adenosine (K i = 3.8 nM) was found to be the most potent and selective (>50-fold) A 2A agonist in this series. Mixed A 2A /A 3 AR agonists have been identified. Interestingly, although most of these compounds were extremely weak at the A 2B AR, 2-[2-(2-naphthyl)ethyloxy]adenosine (EC 50 = 1.4 µM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC 50 = 1.8 (M) were found to be relatively potent A 2B agonists, although less potent than NECA (EC 50 = 140 nM).

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Section: Discussionsupporting

confidence: 83%

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Gao

Mamedova

Chen

et al. 2004

Biochemical Pharmacology

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“…In binding (Table 1), high affinity for the human A 3 AR (K i < 10 nM) was found for compounds 1 and 2 (the reference agonists IB-MECA and Cl-IB-MECA) and for 4′-thionucleosides 10-12 and 16, extending previous observations obtained for the 5′-uronamides 13-15 [15]. Compound 16 is a novel structure having a drastic alteration in the connectivity of the structure, i.e.…”

Section: Binding Affinity Of Ribose-modified Nucleoside Analoguessupporting

confidence: 81%

“…1) was synthesized [14,15,20,21] and compared in binding and functional assays ( Table 1). The set of analogues included nucleosides having a 5′-uronamide modification (1, 2, 8, 9, and 13-16), modification of a hydroxy group either through chiral inversion (3) or through fluorosubstitution (4-9), or a 4′-thio modification (10)(11)(12)(13)(14)(15). 3′-Fluoro (7-9) and 5′-uronamide-4′-thionucleoside (13-15) analogues were reported previously and partially characterized pharmacologically [15].…”

Section: Structures Of Ribose-modified Nucleoside Analoguesmentioning

confidence: 99%

“…Structural determinants critically involved in A 3 AR activation have been identified [8][9][10][11][12][13], leading to the conclusion that the ability of an adenosine derivative to activate the A 3 AR tends to be highly structure-sensitive. 3′-Fluoro has recently been found to interfere with A 3 AR binding [14], and certain 4′-thio nucleosides have been found to be potent and selective human A 3 AR agonists [15]. In this study, we further evaluated the binding affinity and functional properties of a series of ribose-modified adenosine derivatives, including some six previously reported compounds [14,15], at the human A 3 AR stably expressed in CHO cells.…”

Section: Introductionmentioning

confidence: 99%

“…3′-Fluoro has recently been found to interfere with A 3 AR binding [14], and certain 4′-thio nucleosides have been found to be potent and selective human A 3 AR agonists [15]. In this study, we further evaluated the binding affinity and functional properties of a series of ribose-modified adenosine derivatives, including some six previously reported compounds [14,15], at the human A 3 AR stably expressed in CHO cells.…”

Section: Introductionmentioning

confidence: 99%

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Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

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We have found previously that structural features of adenosine derivatives, particularly at the N 6 -and 2-positions of adenine, determine the intrinsic efficacy as A 3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A 3 AR expressed in CHO cells. Both 2′-and 3′-hydroxyl groups in the ribose moiety contribute to A 3 AR binding and activation, with 2′-OH being more essential. Thus, the 2′-fluoro substitution eliminated both binding and activation, while a 3′-fluoro substitution led to only a partial reduction of potency and efficacy at the A 3 AR. A 5′-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3′-fluoro derivatives. The 4′-thio substitution, which generally enhanced A 3 AR potency and selectivity, resulted in 5′-CH 2 OH analogues (10 and 12) which were partial agonists of the A 3 AR. Interestingly, the shifting of the N 6 -(3-iodobenzyl)adenine moiety from the 1′-to 4′-position had a minor influence on A 3 AR selectivity, but transformed 15 into a potent antagonist (16) (K i = 4.3 nM). Compound 16 antagonized human A 3 AR agonist-induced inhibition of cyclic AMP with a K B value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A 3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A 3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A 3 ARs.

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Methanesulfonyl Chloride

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Cudahy²,

Kreilein³

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Encyclopedia of Reagents for Organic Synthesis

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N⁶-Substituted D-4‘-Thioadenosine-5‘-methyluronamides: Potent and Selective Agonists at the Human A₃Adenosine Receptor

Cited by 84 publications

References 18 publications

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Methanesulfonyl Chloride

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N6-Substituted D-4‘-Thioadenosine-5‘-methyluronamides: Potent and Selective Agonists at the Human A3Adenosine Receptor

Cited by 84 publications

References 18 publications

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Methanesulfonyl Chloride

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N⁶-Substituted D-4‘-Thioadenosine-5‘-methyluronamides: Potent and Selective Agonists at the Human A₃Adenosine Receptor