Nucleoside-derived antagonists to A3 adenosine receptors lower mouse intraocular pressure and act across species
| Autor: | Kim Peterson-Yantorno, Zhan Guo Gao, Kenneth A. Jacobson, Lak Shin Jeong, Pedro Besada, Marcel Y. Avila, Zhao Wang, Richard A. Stone, Bhalchandra V. Joshi, Mortimer M. Civan, Chi Wai Do |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Agonist medicine.medical_specialty Intraocular pressure Adenosine genetic structures medicine.drug_class Adenosine A3 Receptor Antagonists Pharmacology Biology Article Mice Tonometry Ocular Cellular and Molecular Neuroscience chemistry.chemical_compound Internal medicine medicine Animals Latanoprost Pigment Epithelium of Eye Antihypertensive Agents Intraocular Pressure Cell Size Ciliary Body Dihydropyridine Antagonist Topical drug application Adenosine receptor eye diseases Sensory Systems Ophthalmology Endocrinology chemistry Cattle Female Ocular Hypertension Nucleoside medicine.drug |
| Zdroj: | Experimental Eye Research. 90:146-154 |
| ISSN: | 0014-4835 |
| DOI: | 10.1016/j.exer.2009.10.001 |
| Popis: | The purpose of the study was to determine whether novel, selective antagonists of human A 3 adenosine receptors (ARs) derived from the A 3 -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 A 3 AR 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 A 3 AR agonists and the dihydropyridine A 3 AR antagonist MRS 1191. Latanoprost similarly lowered SNMS-measured IOP, but not IOP measured non-invasively over 30 min. Like MRS 1191, agonist-based A 3 AR antagonists applied to native bovine NPE cells inhibited adenosine-triggered shrinkage. In summary, the results indicate that antagonists of human A 3 ARs derived from the potent, selective A 3 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 A 3 AR 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 A 3 AR agonist Cl-IB-MECA can reduce IOP upon reaching their intraocular target, and that nucleoside-based derivatives are promising A 3 antagonists for study in multiple animal models. |
| Databáze: | OpenAIRE |
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