title: A novel D2-dopaminergic and alpha2-adrenoceptor receptor agonist induces substantial and prolonged IOP decrease in normotensive rabbits.
abstract: The effects of a novel and selective D2-dopaminergic/alpha2-adrenoceptor agonist, CHF1035, and its metabolite CHF1024 on intraocular pressure (IOP) were determined in rabbits. Because CHF1035 is a mixture of two enantiomers, CHF1800 (+) and CHF1810 (-), pure enantiomers were also studied to determine possible differences in IOP-decreasing ability depending on the stereochemistry of the molecule. CHF1035, CHF1800 (+), CHF1810 (-), CHF1024, brimonidine and 0.9% NaCl were administered topically to rabbits and IOP was then measured at fixed time intervals. The dose-response profile (0.01-1.0% w/v) was determined for CHF1035. CHF1035 and its metabolite CHF1024 significantly lowered IOP in the treated eyes. CHF1035 showed a maximum IOP decrease (7.6 +/- 1.5 mmHg) 5 h post-dosing, whereas the metabolite CHF1024 showed a maximum decrease in IOP (7.0 +/- 0.8 mmHg) 3 h post-dosing. The maximum IOP decrease produced by CHF1035 in the treated eye was comparable with that produced by brimonidine (7.8 +/- 0.9 mmHg), but CHF1035 had a significantly longer duration of action. Unlike brimonidine, CHF1035 and CHF1024 did not decrease IOP in the untreated eye. CHF1810 (-) lowered the IOP more than CHF1800 (+). No irritation, evaluated as eyelid closure, was observed after topical administration of any of the compounds. Only in the case of CHF1035 1% solution, two rabbits out of six closed the eye for 30-45 s. In conclusion, CHF1035 and its metabolite CHF1024 significantly decreased the IOP in rabbits, and are potential novel IOP lowering agents. Especially, CHF1035 produced a substantial decrease in IOP for a prolonged period of time, and thus may prove useful in glaucoma therapy.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. jouko.savolainen@uku.fi
authors.forename: Jouko
authors.initials: J
authors.lastname: Savolainen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.forename: Roberta
authors.initials: R
authors.lastname: Razzetti
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004952:Esters; D007429:Intraocular Pressure / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology*; D011817:Rabbits; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D004952:Esters; D009281:Naphthalenes; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; C457559:nolomirole; C112301:CHF 1024