Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/29018
Title: Nucleoside-derived antagonists to A3 adenosine receptors lower mouse intraocular pressure and act across species
Authors: Wang, Z
Do, CW 
Avila, MY
Peterson-Yantorno, K
Stone, RA
Gao, ZG
Joshi, B
Besada, P
Jeong, LS
Jacobson, KA
Civan, MM
Keywords: aqueous humor
bovine nonpigmented ciliary epithelial cells
nucleoside-based antagonists
pneumotonometry
servo-null micropipette system
Issue Date: 2010
Publisher: Academic Press
Source: Experimental eye research, 2010, v. 90, no. 1, p. 146-154 How to cite?
Journal: Experimental eye research 
Abstract: The purpose of the study was to determine whether novel, selective antagonists of human A3 adenosine receptors (ARs) derived from the A3-selective agonist Cl-IB-MECA lower intraocular pressure (IOP) and act across species. IOP was measured invasively with a micropipette by the Servo-Null Micropipette System (SNMS) and by non-invasive pneumotonometry during topical drug application. Antagonist efficacy was also assayed by measuring inhibition of adenosine-triggered shrinkage of native bovine nonpigmented ciliary epithelial (NPE) cells. Five agonist-based A3AR antagonists lowered mouse IOP measured with SNMS tonometry by 3-5 mm Hg within minutes of topical application. Of the five agonist derivatives, LJ 1251 was the only antagonist to lower IOP measured by pneumotonometry. No effect was detected pneumotonometrically over 30 min following application of the other four compounds, consonant with slower, smaller responses previously measured non-invasively following topical application of A3AR agonists and the dihydropyridine A3AR antagonist MRS 1191. Latanoprost similarly lowered SNMS-measured IOP, but not IOP measured non-invasively over 30 min. Like MRS 1191, agonist-based A3AR antagonists applied to native bovine NPE cells inhibited adenosine-triggered shrinkage. In summary, the results indicate that antagonists of human A3ARs derived from the potent, selective A3 agonist Cl-IB-MECA display efficacy in mouse and bovine cells, as well. When intraocular delivery was enhanced by measuring mouse IOP invasively, five derivatives of the A3AR agonist Cl-IB-MECA lowered IOP but only one rapidly reduced IOP measured non-invasively after topical application. We conclude that derivatives of the highly-selective A3AR agonist Cl-IB-MECA can reduce IOP upon reaching their intraocular target, and that nucleoside-based derivatives are promising A3 antagonists for study in multiple animal models.
URI: http://hdl.handle.net/10397/29018
ISSN: 0014-4835
DOI: 10.1016/j.exer.2009.10.001
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