Effect of SR121463, a selective non-peptide vasopressin V-2 receptor antagonist, in a rabbit model of ocular hypertension

The activity on intraocular pressure (IOP) of SR121463, a selective non-pep tide arginin-vasopressin (AVP) V-2 receptor antagonist, was investigated in a rabbit model of ocular hypertension. We first demonstrated that, in vitro, SR121463 displayed high competitive a ffinity for rabbit vasopressin V-2 receptors (Ki = 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 alpha-chymotr ypsin). SR121463 also was instilled at 1% in the normotensive eye or intrav enously injected (100 mu g/kg) to ocular hypertensive rabbits. SR121463 was compared to timolol 0.5% or to clonidine 0.25%. Additionally, local and sy stemic safety aspects were examined. Results showed that SR121463 was locally well-tolerated and had no anesthet ic effect. A significant decrease in IOP of the hypertensive eye was observ ed for concentrations of SR121463 greater than or equal to 1%. This decreas e was comparable to that obtained with reference compounds. A similar activ ity was found after intravenous administration. No tachyphylaxis was observ ed after 10 days, and no contralateral or systemic effect was noted. Also, when applied on the normotensive eye or when intravenously injected, SR1214 63 had no effect on the normotensive eye. These results on IOP and the good local and systemic safety profile, sugges t that a potent vasopressin V-2 receptor antagonist, SR121463, could be of value for the treatment of glaucoma, through a mechanism of action that rem ains to be elucidated.