Open AccessNovel Monoamine Oxidase Inhibitors, 3-(2-Aminoethoxy)-1,2-benzisoxazole Derivatives, and Their Differential Reversibility
Author(s) -
Kanako Yoshimi,
Masao Kozuka,
Jyunichi Sakai,
Tomoko Iizawa,
Yuki Shimizu,
Isao Kaneko,
Kouichi Kojima,
Nobuyoshi Iwata
Publication year - 2002
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.88.174
Subject(s) - monoamine oxidase , chemistry , monoamine oxidase b , in vitro , monoamine neurotransmitter , enzyme , stereochemistry , monoamine oxidase a , pharmacology , biochemistry , serotonin , biology , receptor
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 degrees 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.