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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todo:paper_00062952_v67_n5_p893_Gao2023-10-03T14:04:18Z Structural determinants of efficacy at A3 adenosine receptors: Modification of the ribose moiety Gao, Z.-G. Jeong, L.S. Moon, H.R. Kim, H.O. Choi, W.J. Shin, D.H. Elhalem, E. Comin, M.J. Melman, N. Mamedova, L. Gross, A.S. Rodriguez, J.B. Jacobson, K.A. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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 Gao, Z.-G. Jeong, L.S. Moon, H.R. Kim, H.O. Choi, W.J. Shin, D.H. Elhalem, E. Comin, M.J. Melman, N. Mamedova, L. Gross, A.S. Rodriguez, J.B. Jacobson, K.A. 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. |
| format |
JOUR |
| author |
Gao, Z.-G. Jeong, L.S. Moon, H.R. Kim, H.O. Choi, W.J. Shin, D.H. Elhalem, E. Comin, M.J. Melman, N. Mamedova, L. Gross, A.S. Rodriguez, J.B. Jacobson, K.A. |
| author_facet |
Gao, Z.-G. Jeong, L.S. Moon, H.R. Kim, H.O. Choi, W.J. Shin, D.H. Elhalem, E. Comin, M.J. Melman, N. Mamedova, L. Gross, A.S. Rodriguez, J.B. Jacobson, K.A. |
| author_sort |
Gao, Z.-G. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_00062952_v67_n5_p893_Gao |
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