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 87 publications

(64 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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).

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…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%

See 2 more Smart Citations

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

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Methanesulfonyl Chloride

Vaillancourt¹,

Cudahy²,

Kreilein³

et al. 2007

Encyclopedia of Reagents for Organic Synthesis

View full text Add to dashboard Cite

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

Cited by 87 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

Contact Info

Product

Resources

About

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

Cited by 87 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

Contact Info

Product

Resources

About

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