Effect of SR121463, a Selective Non-Peptide Vasopressin V2Receptor Antagonist, in a Rabbit Model of Ocular Hypertension

Abstract

The activity on intraocular pressure (IOP) of SR121463, a selective non-peptide arginin-vasopressin (AVP) V₂ receptor antagonist, was investigated in a rabbit model of ocular hypertension. We first demonstrated that, in vitro, SRI21463 displayed high competitive affinity for rabbit vasopressin V₂ receptors (K_i = 2.1 ± 1.2 nM). In vivo, SR121463 was instilled once (at concentrations ranging from 0.1 to 3%), or for 10 days (20 instillations) at 1% concentration, in the eye of ocular hypertensive rabbits (intraocular injection of 0.14 mg α-chymotrypsin). SR121463 also was instilled at 1% in the normotensive eye or intravenously injected (100 pg/kg) to ocular hypertensive rabbits. SR121463 was compared to timolol 0.5% or to clonidine 0.25%. Additionally, local and systemic safety aspects were examined. Results showed that SRI21463 was locally well-tolerated and had no anesthetic effect. A significant decrease in IOP of the hypertensive eye was observed for concentrations of SR121463 ≥1%. This decrease was comparable to that obtained with reference compounds. A similar activity was found after intravenous administration. No tachyphylaxis was observed after 10 days, and no contralateral or systemic effect was noted. Also, when applied on the normotensive eye or when intravenously injected, SR121463 had no effect on the normotensive eye. These results on IOP and the good local and systemic safety profile, suggest that a potent vasopressin V₂ receptor antagonist, SR121463, could be of value for the treatment of glaucoma, through a mechanism of action that remains to be elucidated.