title: Effect of SR121463, a selective non-peptide vasopressin V2 receptor 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, SR121463 displayed high competitive affinity for rabbit vasopressin V2 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-chymotrypsin). SR121463 also was instilled at 1% in the normotensive eye or intravenously injected (100 microg/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 SR121463 was locally well-tolerated and had no anesthetic effect. A significant decrease in IOP of the hypertensive eye was observed for concentrations of SR121463 > or =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.
authors.affiliation: Department of Toxicology and General Pharmacology, SANOFI Recherche, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Lacheretz
authors.forename: A
authors.initials: A
authors.lastname: Barbier
authors.forename: C
authors.initials: C
authors.lastname: Serradeil-Le Gal
authors.forename: P P
authors.initials: PP
authors.lastname: Elena
authors.forename: J P
authors.initials: JP
authors.lastname: Maffrand
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D002462:Cell Membrane / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D007429:Intraocular Pressure / Q000187:drug effects*; D007668:Kidney / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D009798:Ocular Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D011817:Rabbits; D017483:Receptors, Vasopressin / Q000378:metabolism; D012449:Safety; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D013999:Timolol / Q000494:pharmacology
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D009025:Morpholines; D017483:Receptors, Vasopressin; D013141:Spiro Compounds; D013999:Timolol; C103281:satavaptan; D003000:Clonidine