Eugenol and its structural analogs inhibit monoamine oxidase A and exhibit antidepressant-like activity.
Eugenol (1) is an active principle of Rhizoma acori graminei, a medicinal herb used in Asia for the treatment of symptoms reminiscent of Alzheimer's disease (AD). It has been shown to protect neuronal cells from the cytotoxic effect of amyloid beta peptides (Abetas) in cell cultures and exhibit antidepressant-like activity in mice. Results from this study show that eugenol inhibits monoamine oxidase A (MAOA) preferentially with a K(i)=26 microM. It also inhibits MAOB but at much higher concentrations (K(i)=211 microM). In both cases, inhibition is competitive with respect to the monoamine substrate. Survey of compounds structurally related to eugenol has identified a few that inhibit MAOs more potently. Structure activity relationship reveals structural features important for MAOA and MAOB inhibition. Molecular docking experiments were performed to help explain the SAR outcomes. Four of these compounds, two (1, 24) inhibiting MAOA selectively and the other two (19, 21) inhibiting neither MAOA nor MAOB, were tested for antidepressant-like activity using the forced swim test in mice. Results suggest a potential link between the antidepressant activity of eugenol and its MAOA inhibitory activity.
Tao
Guoxin
G
Department of Pathology and Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Irie
Yoshifumi
Y
Li
Dian-Jun
DJ
Keung
Wing Ming
WM
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D003010:Clorgyline / Q000737:chemistry; D005054:Eugenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010293:Pargyline / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D008996:Monoamine Oxidase Inhibitors; D005054:Eugenol; D010293:Pargyline; D008995:Monoamine Oxidase; D003010:Clorgyline