Synthesis and pharmacological characterization of [(125)I]MRS5127, a high affinity, selective agonist radioligand for the A3 adenosine receptor.

Biochemical Pharmacology
John A AuchampachKenneth A Jacobson

Abstract

A recently reported selective agonist of the human A(3) adenosine receptor (hA(3)AR), MRS5127 (1'R,2'R,3'S,4'R,5'S)-4'-[2-chloro-6-(3-iodobenzylamino)-purine]-2',3'-O-dihydroxy-bicyclo-[3.1.0]hexane, was radioiodinated and characterized pharmacologically. It contains a rigid bicyclic ring system in place of a 5'-truncated ribose moiety, and was selected for radiolabeling due to its nanomolar binding affinity at both human and rat A(3)ARs. The radioiodination of the N(6)-3-iodobenzyl substituent by iododestannylation of a 3-(trimethylstannyl)benzyl precursor was achieved in 73% yield, measured after purification by HPLC. [(125)I]MRS5127 bound to the human A(3)AR expressed in membranes of stably transfected HEK 293 cells. Specific binding was saturable, competitive, and followed a one-site binding model, with a K(d) value of 5.74+/-0.97nM. At a concentration equivalent to its K(d), non-specific binding comprised 27+/-2% of total binding. In kinetic studies, [(125)I]MRS5127 rapidly associated with the hA(3)AR (t(1/2)=0.514+/-0.014min), and the affinity calculated from association and dissociation rate constants was 3.50+/-1.46nM. The pharmacological profile of ligands in competition experiments with [(125)I]MRS5127 was consistent ...Continue Reading

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Citations

Apr 4, 2012·Journal of Medicinal Chemistry·Pier Giovanni BaraldiKatia Varani
Jun 23, 2011·The Journal of Pharmacology and Experimental Therapeutics·Dharini van der HoevenJohn A Auchampach
Dec 28, 2010·Biochimica Et Biophysica Acta·Christa E Müller, Kenneth A Jacobson
Feb 17, 2007·Progress in Neurobiology·Patrizia PopoliMaria P Abbracchio
Mar 14, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Antonella Ciancetta, Kenneth A Jacobson
Dec 15, 2020·Purinergic Signalling·Xue YangDaan van der Es
Jan 7, 2018·Biochemical Pharmacology·Lizi XiaLaura H Heitman
Nov 13, 2012·ACS Medicinal Chemistry Letters·Dilip K ToshKenneth A Jacobson

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