title: Nucleoside-derived antagonists to A3 adenosine receptors lower mouse intraocular pressure and act across species.
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.
authors.affiliation: Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Do
authors.forename: Marcel Y
authors.initials: MY
authors.lastname: Avila
authors.forename: Kim
authors.initials: K
authors.lastname: Peterson-Yantorno
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stone
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Bhalchandra
authors.initials: B
authors.lastname: Joshi
authors.forename: Pedro
authors.initials: P
authors.lastname: Besada
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Mortimer M
authors.initials: MM
authors.lastname: Civan
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002417:Cattle; D048429:Cell Size / Q000187:drug effects; D002924:Ciliary Body / Q000166:cytology; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D051379:Mice; D009798:Ocular Hypertension / Q000188:drug therapy*; D010857:Pigment Epithelium of Eye / Q000187:drug effects; D014065:Tonometry, Ocular
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D000959:Antihypertensive Agents; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide