ABSTRACT
PURPOSE: To define the molecular pharmacology underlying the antiangiogenic effects of nonpeptide imidazolidine-2,4-dione somatostatin receptor agonists (NISAs) and evaluate the efficacy of NISA in ocular versus systemic delivery routes in ocular disease models. METHODS: Functional inhibitory effects of the NISAs and the somatostatin peptide analogue octreotide were evaluated in vitro by chemotaxis, proliferation, and tube-formation assays. The oxygen-induced retinopathy (OIR) model and the laser model of choroidal neovascularization (CNV) were used to test the in vivo efficacy of NISAs. Transscleral permeability of a candidate NISA was also measured. RESULTS: NISAs inhibited growth factor-induced HREC proliferation, migration and tube formation with submicromolar potencies (IC(50), 0.1-1.0 microM) comparable to octreotide. In the OIR model, systemic administration of the NISAs RFE-007 and RFE-011 inhibited retinal neovascularization in a dose-dependent manner, comparable to octreotide. In the CNV model, intravitreal RFE-011 resulted in a 56% reduction (P < 0.01) in CNV lesion area, whereas systemic administration resulted in a 35% reduction (P < 0.05) in lesion area. RFE-011 demonstrated transscleral penetration. CONCLUSIONS: Micromolar concentrations of octreotide and NISAs are necessary for antiangiogenic effects, whereas nanomolar concentrations are effective for endocrine inhibition. This suggests that the antiangiogenic activity of NISAs and octreotide is mediated by an overall much less efficient downstream coupling mechanism than is growth hormone release. As a result, the intravitreal or transscleral route of administration should be seriously considered for future clinical studies of SSTR2 agonists used for treatment of ocular neovascularization to ensure efficacious concentrations in the target retinal and choroidal tissue.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Choroidal Neovascularization/drug therapy , Gene Expression/drug effects , Imidazolidines/agonists , RNA/genetics , Receptors, Somatostatin/genetics , Retinal Neovascularization/drug therapy , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Animals , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/pharmacokinetics , Antineoplastic Agents, Hormonal/therapeutic use , Autoradiography , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Choroidal Neovascularization/metabolism , Choroidal Neovascularization/pathology , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Humans , Injections , Mice , Mice, Inbred C57BL , Octreotide/administration & dosage , Octreotide/pharmacokinetics , Octreotide/therapeutic use , Ophthalmic Solutions , Polymerase Chain Reaction , Rabbits , Receptors, Somatostatin/metabolism , Retinal Neovascularization/metabolism , Retinal Neovascularization/pathology , Sclera , Treatment Outcome , Vitreous BodyABSTRACT
The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.
