Structure-guided design of A(3) adenosine receptor-selective nucleosides: combination of 2-arylethynyl and bicyclo[3.1.0]hexane substitutions.

Journal of Medicinal Chemistry
Dilip K ToshK A Jacobson

Abstract

(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N(6)-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K(i) 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N(6)-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K(i) hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K(i) hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR agonists.

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Citations

Nov 27, 2015·The Journal of Pharmacology and Experimental Therapeutics·Jesse Lea CarlinMarc L Reitman
Jan 26, 2016·British Journal of Pharmacology·K JanesD Salvemini
Sep 24, 2013·Biochimica Et Biophysica Acta·Rajashri SridharanMark E Dumont
Jul 21, 2015·ACS Medicinal Chemistry Letters·Dilip K ToshKenneth A Jacobson
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Mar 14, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Antonella Ciancetta, Kenneth A Jacobson
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Mar 19, 2020·Pain·Kenneth A JacobsonDaniela Salvemini
Jul 29, 2020·Purinergic Signalling·R Rama SureshKenneth A Jacobson
Aug 18, 2020·ChemMedChem·Veronica Salmaso, Kenneth A Jacobson
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Mar 19, 2021·Chemistry : a European Journal·Carlotta BorgarelliErmal Ismalaj
Nov 13, 2012·ACS Medicinal Chemistry Letters·Dilip K ToshKenneth A Jacobson
Sep 24, 2014·Bioconjugate Chemistry·María Isabel BahamondeFrancisco Ciruela

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