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Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists
- Title
- Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists
- Authors
- Gao Z.-G.; Duong H.T.; Sonina T.; Kim S.-K.; Van Rompaey P.; Van Calenbergh S.; Mamedova L.; Kim H.O.; Kim M.J.; Kim A.Y.; Liang B.T.; Jeong L.S.; Jacobson K.A.
- Ewha Authors
- 정낙신
- SCOPUS Author ID
- 정낙신
- Issue Date
- 2006
- Journal Title
- Journal of Medicinal Chemistry
- ISSN
- 0022-2623
- Citation
- Journal of Medicinal Chemistry vol. 49, no. 9, pp. 2689 - 2702
- Indexed
- SCI; SCIE; SCOPUS
- Document Type
- Article
- Abstract
- 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 A3 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, N6-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N6-3-iodobenzyl-3′- ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC 50 = 0.18 μM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A2AR. The affinity enhancements for 10 and the corresponding 3′-acetamidomethyl analogue 6 were > 100-fold and > 20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A 3AR (EC50 of 1.0 μM), but had no effect on the H272E mutant A3AR (100 μM). Compound 10 was inactive at human A 1, A2A, and A2BARs. 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. © 2006 American Chemical Society.
- DOI
- 10.1021/jm050968b
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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