Orthogonal Activation of the Reengineered A3 Adenosine Receptor (Neoceptor) Using Tailored Nucleoside Agonists
| Autor: | Philippe Van Rompaey, Liaman K. Mamedova, Lak Shin Jeong, Kenneth A. Jacobson, Zhan-Guo Gao, Tatiana Sonina, Bruce T. Liang, Hea Ok Kim, Serge Van Calenbergh, Myong Jung Kim, Ae Yil Kim, Heng T. Duong, Soo-Kyung Kim |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Agonist medicine.drug_class Myocardial Reperfusion Injury Chick Embryo Pharmacology Ligands Article Structure-Activity Relationship Adenosine A3 Receptor Agonists Cricetinae Chlorocebus aethiops Drug Discovery medicine Animals Humans Structure–activity relationship Binding site Receptor Cells Cultured G protein-coupled receptor Binding Sites Chemistry Receptor Adenosine A3 fungi food and beverages Nucleosides Protein Structure Tertiary Biochemistry Mutation Molecular Medicine Genetic Engineering Nucleoside Adenosine A2B receptor |
| Zdroj: | Journal of Medicinal Chemistry. 49:2689-2702 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm050968b |
| Popis: | An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3': amino, aminomethyl, azido, guanidino, ureido; and at 5': uronamido, azidodeoxy. N(6)-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N(6)-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC(50) = 0.18 microM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were100-fold and20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC(50) of 1.0 microM), but had no effect on the H272E mutant A(3)AR (100 microM). Compound 10 was inactive at human A(1), A(2A), and A(2B)ARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene. |
| Databáze: | OpenAIRE |
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