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

We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-mod...

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Autores principales:	Elhalem, Eleonora, Comin, María Julieta, Rodríguez, Juan Bautista
Publicado:	2004
Materias:	A3 adenosine receptor agonist A3 adenosine receptor antagonist Adenylyl cyclase Nucleosides Partial agonist Phospholipase C adenosine A3 receptor agonist adenosine A3 receptor antagonist ribose animal cell article CHO cell controlled study drug efficacy drug inhibition drug potency drug selectivity drug transformation nonhuman priority journal receptor affinity receptor intrinsic activity species difference substitution reaction
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v67_n5_p893_Gao http://hdl.handle.net/20.500.12110/paper_00062952_v67_n5_p893_Gao
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00062952_v67_n5_p893_Gao
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spelling	paper:paper_00062952_v67_n5_p893_Gao2023-06-08T14:30:34Z Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety Elhalem, Eleonora Comin, María Julieta Rodríguez, Juan Bautista A3 adenosine receptor agonist A3 adenosine receptor antagonist Adenylyl cyclase Nucleosides Partial agonist Phospholipase C adenosine A3 receptor agonist adenosine A3 receptor antagonist ribose animal cell article CHO cell controlled study drug efficacy drug inhibition drug potency drug selectivity drug transformation nonhuman priority journal receptor affinity receptor intrinsic activity species difference substitution reaction We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 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 A3 AR expressed in CHO cells. Both 2′- and 3′-hydroxyl groups in the ribose moiety contribute to A3 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 A3 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 A3 AR potency and selectivity, resulted in 5′-CH2OH analogues (10 and 12) which were partial agonists of the A3 AR. Interestingly, the shifting of the N6-(3- iodobenzyl)adenine moiety from the 1′- to 4′-position had a minor influence on A3 AR selectivity, but transformed 15 into a potent antagonist (16) (Ki=4.3nM). Compound 16 antagonized human A 3 AR agonist-induced inhibition of cyclic AMP with a KB value of 3.0nM. 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 A3 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 A3 ARs. © 2003 Elsevier Inc. All rights reserved. Fil:Elhalem, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Comin, M.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rodriguez, J.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2004 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v67_n5_p893_Gao http://hdl.handle.net/20.500.12110/paper_00062952_v67_n5_p893_Gao
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	A3 adenosine receptor agonist A3 adenosine receptor antagonist Adenylyl cyclase Nucleosides Partial agonist Phospholipase C adenosine A3 receptor agonist adenosine A3 receptor antagonist ribose animal cell article CHO cell controlled study drug efficacy drug inhibition drug potency drug selectivity drug transformation nonhuman priority journal receptor affinity receptor intrinsic activity species difference substitution reaction
spellingShingle	A3 adenosine receptor agonist A3 adenosine receptor antagonist Adenylyl cyclase Nucleosides Partial agonist Phospholipase C adenosine A3 receptor agonist adenosine A3 receptor antagonist ribose animal cell article CHO cell controlled study drug efficacy drug inhibition drug potency drug selectivity drug transformation nonhuman priority journal receptor affinity receptor intrinsic activity species difference substitution reaction Elhalem, Eleonora Comin, María Julieta Rodríguez, Juan Bautista Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
topic_facet	A3 adenosine receptor agonist A3 adenosine receptor antagonist Adenylyl cyclase Nucleosides Partial agonist Phospholipase C adenosine A3 receptor agonist adenosine A3 receptor antagonist ribose animal cell article CHO cell controlled study drug efficacy drug inhibition drug potency drug selectivity drug transformation nonhuman priority journal receptor affinity receptor intrinsic activity species difference substitution reaction
description	We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 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 A3 AR expressed in CHO cells. Both 2′- and 3′-hydroxyl groups in the ribose moiety contribute to A3 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 A3 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 A3 AR potency and selectivity, resulted in 5′-CH2OH analogues (10 and 12) which were partial agonists of the A3 AR. Interestingly, the shifting of the N6-(3- iodobenzyl)adenine moiety from the 1′- to 4′-position had a minor influence on A3 AR selectivity, but transformed 15 into a potent antagonist (16) (Ki=4.3nM). Compound 16 antagonized human A 3 AR agonist-induced inhibition of cyclic AMP with a KB value of 3.0nM. 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 A3 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 A3 ARs. © 2003 Elsevier Inc. All rights reserved.
author	Elhalem, Eleonora Comin, María Julieta Rodríguez, Juan Bautista
author_facet	Elhalem, Eleonora Comin, María Julieta Rodríguez, Juan Bautista
author_sort	Elhalem, Eleonora
title	Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
title_short	Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
title_full	Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
title_fullStr	Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
title_full_unstemmed	Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
title_sort	structural determinants of efficacy at a3 adenosine receptors: modification of the ribose moiety
publishDate	2004
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v67_n5_p893_Gao http://hdl.handle.net/20.500.12110/paper_00062952_v67_n5_p893_Gao
work_keys_str_mv	AT elhalemeleonora structuraldeterminantsofefficacyata3adenosinereceptorsmodificationoftheribosemoiety AT cominmariajulieta structuraldeterminantsofefficacyata3adenosinereceptorsmodificationoftheribosemoiety AT rodriguezjuanbautista structuraldeterminantsofefficacyata3adenosinereceptorsmodificationoftheribosemoiety
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Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety

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