Novel monoamine oxidase inhibitors, 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, and their differential reversibility.
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.
Yoshimi
Kenji
K
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. kenjiy@shina.sankyo.co.jp
Kozuka
Masao
M
Sakai
Jyunichi
J
Iizawa
Tomoko
T
Shimizu
Yuki
Y
Kaneko
Isao
I
Kojima
Kouichi
K
Iwata
Nobuyoshi
N
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D013329:Structure-Activity Relationship
D007555:Isoxazoles; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase