Ocular effects of a N,N-disubstituted 5-OH aminotetralin (N-0437): evidence for a dual mechanism of action.
The selective DA2 agonist, N-0437, produced an acute reduction in intraocular pressure (IOP) and pupil diameter (PD) when applied topically to the eyes of normal monkeys. Ocular hypotension and miosis were primarily unilateral in nature, dose-related and lasted 3 to 5 hours following drug instillation. In normal monkeys, 24 to 48 hours following drug administration, a secondary chronic (greater than 24 hrs) reduction in pressure was observed. Once-a-day topical administration of N-0437 (250 micrograms), to normal monkeys, for 4 days produced a chronic unilateral reduction in IOP that persisted for 18 days. Associated with this reduction in pressure on day 2 through 6 were miosis and ptosis of the treated eye. Although topical administration did not lower IOP in rabbits, intracameral injection of N-0437 significantly depressed IOP for 3 days when compared to control injected eyes. Evaluation of ocular sympathetic innervation in N-0437 treated rabbits indicated that these fibers were not functional. In rabbits, intracameral administration of the active (S,-) and inactive (R,+) enantiomer of N-0437 produced equivalent reductions in pressure. These data provide further support for the hypothesis that DA2 receptor agonists can produce acute reductions in IOP. In addition, N-0437 appears to have a second non-receptor mediated mechanism of action that produces a chronic reduction in IOP. This chronic reduction in pressure appears, in part, to result from an interruption of ocular sympathetic nerves function.
Department of Pharmacology, Allergan Inc., Irvine, CA 92715.
C E
CE
Crosson
J A
JA
Burke
M F
MF
Chan
D E
DE
Potter
D000287:Administration, Topical; D000818:Animals; D001696:Biomechanical Phenomena; D002428:Cebus; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000187:drug effects*; D007429:Intraocular Pressure / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D011680:Pupil / Q000187:drug effects; D011817:Rabbits; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors
D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine