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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/85345
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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 |
_version_ |
1844613111697375232 |
score |
13.070432 |