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

Autores
Gao, Zhan-Guo; Jeong, Lak Shin; Moon, Hyung Ryong; Kim, Hea Ok; Choi, Won Jun; Shin, Dae Hong; Elhalem, Eleonora; Comin, Maria Julieta; Melman, Neli; Mamedova, Liaman; Gross, Ariel S.; Rodriguez, Juan Bautista; Jacobson, Kenneth A.
Año de publicación
2004
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Gao, Zhan-Guo. National Institutes of Health; Estados Unidos
Fil: Jeong, Lak Shin. Ewha Womans University; Corea del Sur
Fil: Moon, Hyung Ryong. Ewha Womans University; Corea del Sur
Fil: Kim, Hea Ok. Ewha Womans University; Corea del Sur
Fil: Choi, Won Jun. Ewha Womans University; Corea del Sur
Fil: Shin, Dae Hong. Ewha Womans University; Corea del Sur
Fil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Melman, Neli. National Institutes of Health; Estados Unidos
Fil: Mamedova, Liaman. National Institutes of Health; Estados Unidos
Fil: Gross, Ariel S.. National Institutes of Health; Estados Unidos
Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Jacobson, Kenneth A.. National Institutes of Health; Estados Unidos
Materia
A3 ADENOSINE RECEPTOR AGONIST
A3 ADENOSINE RECEPTOR ANTAGONIST
ADENYLYL CYCLASE
NUCLEOSIDES
PARTIAL AGONIST
PHOSPHOLIPASE C
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/85345

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oai_identifier_str oai:ri.conicet.gov.ar:11336/85345
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moietyGao, Zhan-GuoJeong, Lak ShinMoon, Hyung RyongKim, Hea OkChoi, Won JunShin, Dae HongElhalem, EleonoraComin, Maria JulietaMelman, NeliMamedova, LiamanGross, Ariel S.Rodriguez, Juan BautistaJacobson, Kenneth A.A3 ADENOSINE RECEPTOR AGONISTA3 ADENOSINE RECEPTOR ANTAGONISTADENYLYL CYCLASENUCLEOSIDESPARTIAL AGONISTPHOSPHOLIPASE Chttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1We 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.Fil: Gao, Zhan-Guo. National Institutes of Health; Estados UnidosFil: Jeong, Lak Shin. Ewha Womans University; Corea del SurFil: Moon, Hyung Ryong. Ewha Womans University; Corea del SurFil: Kim, Hea Ok. Ewha Womans University; Corea del SurFil: Choi, Won Jun. Ewha Womans University; Corea del SurFil: Shin, Dae Hong. Ewha Womans University; Corea del SurFil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Melman, Neli. National Institutes of Health; Estados UnidosFil: Mamedova, Liaman. National Institutes of Health; Estados UnidosFil: Gross, Ariel S.. National Institutes of Health; Estados UnidosFil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Jacobson, Kenneth A.. National Institutes of Health; Estados UnidosPergamon-Elsevier Science Ltd2004-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85345Gao, Zhan-Guo; Jeong, Lak Shin; Moon, Hyung Ryong; Kim, Hea Ok; Choi, Won Jun; et al.; Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 67; 5; 3-2004; 893-9010006-2952CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bcp.2003.10.006info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0006295203008190info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:35:37Zoai:ri.conicet.gov.ar:11336/85345instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:35:38.167CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
title Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
spellingShingle Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety
Gao, Zhan-Guo
A3 ADENOSINE RECEPTOR AGONIST
A3 ADENOSINE RECEPTOR ANTAGONIST
ADENYLYL CYCLASE
NUCLEOSIDES
PARTIAL AGONIST
PHOSPHOLIPASE C
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
dc.creator.none.fl_str_mv Gao, Zhan-Guo
Jeong, Lak Shin
Moon, Hyung Ryong
Kim, Hea Ok
Choi, Won Jun
Shin, Dae Hong
Elhalem, Eleonora
Comin, Maria Julieta
Melman, Neli
Mamedova, Liaman
Gross, Ariel S.
Rodriguez, Juan Bautista
Jacobson, Kenneth A.
author Gao, Zhan-Guo
author_facet Gao, Zhan-Guo
Jeong, Lak Shin
Moon, Hyung Ryong
Kim, Hea Ok
Choi, Won Jun
Shin, Dae Hong
Elhalem, Eleonora
Comin, Maria Julieta
Melman, Neli
Mamedova, Liaman
Gross, Ariel S.
Rodriguez, Juan Bautista
Jacobson, Kenneth A.
author_role author
author2 Jeong, Lak Shin
Moon, Hyung Ryong
Kim, Hea Ok
Choi, Won Jun
Shin, Dae Hong
Elhalem, Eleonora
Comin, Maria Julieta
Melman, Neli
Mamedova, Liaman
Gross, Ariel S.
Rodriguez, Juan Bautista
Jacobson, Kenneth A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv A3 ADENOSINE RECEPTOR AGONIST
A3 ADENOSINE RECEPTOR ANTAGONIST
ADENYLYL CYCLASE
NUCLEOSIDES
PARTIAL AGONIST
PHOSPHOLIPASE C
topic A3 ADENOSINE RECEPTOR AGONIST
A3 ADENOSINE RECEPTOR ANTAGONIST
ADENYLYL CYCLASE
NUCLEOSIDES
PARTIAL AGONIST
PHOSPHOLIPASE C
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Gao, Zhan-Guo. National Institutes of Health; Estados Unidos
Fil: Jeong, Lak Shin. Ewha Womans University; Corea del Sur
Fil: Moon, Hyung Ryong. Ewha Womans University; Corea del Sur
Fil: Kim, Hea Ok. Ewha Womans University; Corea del Sur
Fil: Choi, Won Jun. Ewha Womans University; Corea del Sur
Fil: Shin, Dae Hong. Ewha Womans University; Corea del Sur
Fil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Melman, Neli. National Institutes of Health; Estados Unidos
Fil: Mamedova, Liaman. National Institutes of Health; Estados Unidos
Fil: Gross, Ariel S.. National Institutes of Health; Estados Unidos
Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Jacobson, Kenneth A.. National Institutes of Health; Estados Unidos
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.
publishDate 2004
dc.date.none.fl_str_mv 2004-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/85345
Gao, Zhan-Guo; Jeong, Lak Shin; Moon, Hyung Ryong; Kim, Hea Ok; Choi, Won Jun; et al.; Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 67; 5; 3-2004; 893-901
0006-2952
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85345
identifier_str_mv Gao, Zhan-Guo; Jeong, Lak Shin; Moon, Hyung Ryong; Kim, Hea Ok; Choi, Won Jun; et al.; Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 67; 5; 3-2004; 893-901
0006-2952
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bcp.2003.10.006
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0006295203008190
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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