2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Glaucoma

Glaucoma, a heterogeneous ocular disorder affecting ∼60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.

Topics: Adrenergic Agonists; Adrenergic Antagonists; Adrenergic beta-Antagonists; Animals; Drug Discovery; Glaucoma; Humans; Ligands; Protein Kinase Inhibitors; rho-Associated Kinases; Sympathomimetics

Adenosine is thought to participate in the regulation of intraocular pressure since adenosine and several adenosine derivatives increase and/or decrease intraocular pressure. This article reviews the involvement of adenosine receptors in the regulation of intraocular pressure and the possible application of relatively selective adenosine A(2)-receptor agonists, 2-alkynyladenosine derivatives (2-AAs), as novel drugs for treatment of glaucoma. We found that some 2-AAs decreased intraocular pressure in normotensive rabbits. Moreover, these 2-AAs are also effective in the ocular hypertensive models induced by water-loading and alpha-chymotrypsin. In addition, the ocular hypotension induced by 2-(1-octyn-1-yl) derivative was inhibited by an adenosine A(2)-receptor antagonist 3,7-dimethyl-1-propargylxanthine, but not by an adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropyl xanthine. Moreover, the outflow facility was increased by the 2-(1-octyn-1-yl) derivative. These findings suggest that 2-AAs may affect intraocular pressure via adenosine A(2)-receptor, and 2-AAs-induced ocular hypotension is due to the increase in outflow facility. Some 2-AAs may be novel drugs against ocular hypertension and/or glaucoma, although additional studies are required to characterize the effects of 2-AAs on regulation of intraocular pressure in detail.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Drug Design; Glaucoma; Humans; Intraocular Pressure; Ocular Hypertension; Phenethylamines; Rabbits; Receptors, Adenosine A2