Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 정낙신 | - |
dc.date.accessioned | 2018-05-30T08:14:00Z | - |
dc.date.available | 2018-05-30T08:14:00Z | - |
dc.date.issued | 2006 | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.other | OAK-3315 | - |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/243470 | - |
dc.description.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. | - |
dc.language | English | - |
dc.title | Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists | - |
dc.type | Article | - |
dc.relation.issue | 9 | - |
dc.relation.volume | 49 | - |
dc.relation.index | SCI | - |
dc.relation.index | SCIE | - |
dc.relation.index | SCOPUS | - |
dc.relation.startpage | 2689 | - |
dc.relation.lastpage | 2702 | - |
dc.relation.journaltitle | Journal of Medicinal Chemistry | - |
dc.identifier.doi | 10.1021/jm050968b | - |
dc.identifier.wosid | WOS:000237343700005 | - |
dc.identifier.scopusid | 2-s2.0-33646439527 | - |
dc.author.google | Gao Z.-G. | - |
dc.author.google | Duong H.T. | - |
dc.author.google | Sonina T. | - |
dc.author.google | Kim S.-K. | - |
dc.author.google | Van Rompaey P. | - |
dc.author.google | Van Calenbergh S. | - |
dc.author.google | Mamedova L. | - |
dc.author.google | Kim H.O. | - |
dc.author.google | Kim M.J. | - |
dc.author.google | Kim A.Y. | - |
dc.author.google | Liang B.T. | - |
dc.author.google | Jeong L.S. | - |
dc.author.google | Jacobson K.A. | - |
dc.contributor.scopusid | 정낙신(16028528200) | - |
dc.date.modifydate | 20211210153610 | - |