Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

doi:10.1016/j.bmcl.2008.04.001

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 9, 1 May 2008, Pages 2813-2819

https://doi.org/10.1016/j.bmcl.2008.04.001 Get rights and content

Abstract

2-Chloro-5′-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A₃ adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A₁AR. Therefore, we varied substituents at the N⁶ and C2 positions in search of compounds that have improved A₃AR selectivity and are species independent. An N⁶-methyl analogue was balanced in affinity at mouse A₁/A₃ARs, with high selectivity in comparison to the A_2AAR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A₃AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A₃AR selectivity more effectively than similar chains attached at the 3-position of the N⁶-benzyl group.

Graphical abstract

R¹ = Me, MeO, substituted benzyl and 2-phenylethyl, R² = Cl, I, MeS, alkynyl.

Section snippets

Acknowledgments

This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (K.A.J.) and by NIH R01 HL077707 (J.A.A.). We thank Can-Fite Biopharma (Petah-Tikva, Israel) for financial support.

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Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

Abstract

Graphical abstract

Section snippets

Acknowledgments

Cell Calcium

J. Med. Chem.

J. Med. Chem.

J. Chem. Inf. Model.

J. Mol. Graph. Model.

J. Biol. Chem.

Mol. Pharmacol.

Circulation

Nat. Rev. Drug Disc.

J. Cell. Physiol.

Mol. Pharmacol.

Am. J. Physiol. Heart Circ. Physiol.

Circ. Res.

Mol. Pharmacol.

Clin. Cancer Res.

Expert Opin. Investig. Drugs

Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A₃ receptor-selective agonists