Luc Lebreton

5-Aryl-1,3,4-oxadiazol-2(3H)-one derivatives and sulfur analogues as new selective and competitive monoamine oxidase type B inhibitors

Eighteen new 5-aryl-1,3,4-oxadiazol-2(3H)-one derivatives and sulfur analogues were prepared and evaluated in vitro for their inhibitory properties on monoamine oxidase (MAO) types A and B. The most active compounds in these series acted preferentially against MAO B with IC50 values in the range of 1.8-0.056 μM. The 5-(4-biphenylyl)-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one 23 and its oxadiazolethione analogue 33 were found to act as potent, selective and competitive MAO B inhibitors with a slight slow-binding character. Both compounds inhibited MAO A in a classical competitive manner. According to their Ki (MAO B) values of 2.6 and 4 × 10−8 M, respectively, and their Ki (MAO A)/Ki (MAO B) ratios of 270 and 500, respectively, 23 and 33 can be placed among the most active and selective competitive MAO B inhibitors known up to now. The structure-activity relationships are discussed.

Inhibition of monoamine oxidase types A and B by 2-aryl-4H-1,3,4-oxadiazin-5(6H)-one derivatives

Abstract Monoamine oxidase (MAO) assay specificity based on substrate specificity was investigated by substrate competition experiments. 10 μM serotonin (5-HT) and 5 μM β-phenylethylamine (PEA) were found to ensure total substrate specificity for, respectively, MAO types A and B. Twenty-five 2-aryl-4 H -1,3,4-oxadiazin-5(6 H )-one derivatives were synthesized and tested in vitro for their inhibitory effects on MAO A and B. Most of them inhibited preferentially MAO B. The 2-(4-biphenylyl)-4-(2-cyanoethyl)-4 H -1,3,4-oxadiazin-5(6 H )-one 32 was the most efficient MAO B inhibitor and acted as a competitive inhibitor on the two enzymes. Its K i values for MAO A and B were 11 and 0.15 μM, respectively. Structure-activity relationships suggest that these oxadiazinones should interact with a hydrophobic site and a nucleophilic site on MAO B for binding, while the functional group of the N-4 substituent should compete with the substrate for the active site of the enzyme.

Protective Effect of Intravitreal Administration of Tresperimus, an Immunosuppressive Drug, on Experimental Autoimmune Uveoretinitis

PURPOSE To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU). METHODS EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization. The pharmacokinetics of tresperimus was evaluated in the ocular tissues and plasma. The in vitro effect of tresperimus was evaluated on macrophages. EAU was graded clinically and histologically. Blood ocular barrier permeability was evaluated by protein concentration in ocular fluids. Immune response to S-Ag was examined by delayed type hypersensitivity, the expression of inflammatory cytokines in lymph nodes, ocular fluids and serum by multiplex ELISA, and in ocular cells by RT-PCR. RESULTS In vitro, tresperimus significantly reduced the production of inflammatory cytokines by lipopolysaccharide-stimulated macrophages. In vivo, in the treatment protocol, efficient tresperimus levels were measured in the eye but not in the plasma up to 8 days after the last injection. Tresperimus efficiently reduced inflammation, retinal damage, and blood ocular barrier permeability breakdown. It inhibited nitric oxide synthase-2 and nuclear factor κBp65 expression in ocular macrophages. IL-2 and IL-17 were decreased in ocular media, while IL-18 was increased. By contrast, IL-2 and IL-17 levels were not modified in inguinal lymph nodes draining the immunization site. Moreover, cytokine levels in serum and delayed type hypersensitivity to S-Ag were not different in control and treated rats. In the prevention/treatment protocol, ocular immunosuppressive effects were also observed. CONCLUSIONS Locally administered tresperimus appears to be a potential immunosuppressive agent in the management of intraocular inflammation.