Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor
| Autor: | Dae Hong Shin, Kenneth A. Jacobson, Lak Shin Jeong, Dong Zhe Jin, Jeong A. Lee, Hea Ok Kim, Moon Woo Chun, Hyung Ryong Moon, Heng T. Duong, Changrui Lu, Sang Kook Lee, Hyuk Woo Lee, Prashantha Gunaga, Zhan-Guo Gao |
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| Rok vydání: | 2006 |
| Předmět: |
Agonist
Adenosine Adenosine A2 Receptor Agonists medicine.drug_class Stereochemistry Drug Evaluation Preclinical Adenylate kinase Carboxamide CHO Cells Cyclase Partial agonist Structure-Activity Relationship Adenosine A3 Receptor Agonists Cricetinae Drug Discovery medicine Moiety Animals Humans Binding site Molecular Structure Chemistry Stereoisomerism Amides In vitro Adenosine A1 Receptor Agonists Uronic Acids Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 49(1) |
| ISSN: | 0022-2623 |
| Popis: | We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR. |
| Databáze: | OpenAIRE |
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