Novel Monoamine Oxidase Inhibitors, 3-(2-Aminoethoxy)-1,2-benzisoxazole Derivatives, and Their Differential Reversibility

Abstract

ABSTRACT-Although possible usefulness of non-selective monoamine oxidase (MAO) inhibitors for Parkinson's disease therapy has been suggested in the literature, MAO inhibitors whose inhibition is reversible and have dual action to both MAO-A and -B subtypes is not available yet. Subtype selectivity and reversibility of a series of novel MAO inhibitors, 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, were studied. Several dual MAO inhibitors, which inhibit both MAO-A and -B, were obtained. When administered to mice, their effects were generally reversible. Among the derivatives, RS-1636 and RS-1653 had much longer duration of brain MAO-B inhibition than that of MAO-A. In vitro, the inhibited MAO-A activity by these compounds was partially recovered by buffer change at 4°C, while little MAO-B activity was recovered. Although it is not fully elucidated yet, the reversibility of these inhibitors is probably determined primarily by this dissociation profile. This unique differential reversibility indicates that optimization of the balance of actions can be achieved by differentiating reversibility to each target molecule.Keywords: Monoamine oxidase, Tight-binding inhibitor, Reversibility, Parkinson's disease Monoamine oxidase (MAO, EC 1.4.3.4) inhibitors were discovered by their effect on mood disorders in the 1950s (1, 2), and have been used as antidepressants since then. Two isozymes, MAO-A and MAO-B have been identified (1, 2). MAO-A is selectively inhibited by clorgyline and preferentially deaminates serotonin (5-HT) and noradrenaline (NA). MAO-B is selectively inhibited by l-deprenyl and preferentially deaminates 2-phenylethylamine (PEA) and benzylamine. Recently, marked advances have been made in the understanding of selective binding of substrates with MAO (3, 4). The old generation of MAO inhibitors, such as isocarboxazid, phenelzine and tranylcypromine, inhibit both A and B isozymes irreversibly. Several inhibitors selective to only MAO-A or MAO-B, with both reversible and irreversible characteristics, were developed later. Clorgyline, moclobemide (2), brofaromine (5), toloxatone and RS-8359 (6, 7) are some such MAO-A selective inhibitors that are strong antidepressants. lDeprenyl (selegiline) (8), rasagiline, MDL-72974 and lazabemide (9) are some such selective inhibitors to MAO-B that have a mild anti-Parkinsonian effect. However, potential usefulness of reversible MAO inhibitors that have dual action to both MAO-A and MAO-B (10) have not been verified yet.In this paper, a new family of MAO inhibitors, 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, is presented. Several reversible MAO inhibitors to both MAO-A and -B were obtained. Among the reversible dual inhibitors, RS-1636 and RS-1653 had much longer duration of MAO-B inhibition than that of MAO-A. The profile of MAO inhibition in vitro was studied to verify the mechanism of this differential reversibility. MATERIALS AND METHODS AnimalsMale C57BL/6 mice (5 -7 week-old, 18 -22 g body weight, from Charles River, Tokyo), which are widely used in rodent m...

Recent Advances in the Arylation and Alkenylation of N–O Bonds

“…6 Good biological activities have been found in these diverse synthetic motifs. 7 Some are potent agents with significant in vitro activity against ectoand endoparasites, and exhibit high larvicidal activities against the mosquito and the oriental armyworm. 2c In addition to the bioactive and medicinal applications for compounds with N-O bonds, up to now, they have been successfully applied in [1,3], [3,3] and [2,3] rearrangements, cyclizations, cycloadditions, C-H activations, radical trapping reactions, and related transformations.…”

High-throughput screening for monoamine oxidase-A and monoamine oxidase-B inhibitors using one-step fluorescence assay1

“…Based on the general reaction RCH 2 NR 1 R 2 + H 2 O+O 2 -→ RCHO + NHR 1 R 2 + H 2 O 2 , available assays to measure MAO activity can be summarized either by determining the rate of product formation or substrates depleted in an MAOcatalyzed reaction: (1) the direct measurement of oxygen consumption by polarographic detection [6] ; (2) the detection of oxidized monoamine products by spectrophotometry or radiometric assay [7,8] ited convenience [9] ; (4) the assessment of co-product hydrogen peroxide directly [10] or indirectly, a continuous fluorescence assay with a sensitive, stable H 2 O 2 probe, N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red). Because of its convenience and continuity, this one-step method was considered more suitable to detect the activity of enzymes whose co-product is hydrogen peroxide.…”