Alantrypinone and its derivatives: synthesis and antagonist activity toward insect GABA receptors.
The gamma-aminobutyric acid (GABA) receptor bears important sites of action for insecticides. Alantrypinone is an insecticidal alkaloid that acts as a selective antagonist for housefly (vs rat) GABA receptors, and is considered to be a lead compound for the development of a safer insecticide. In an attempt to obtain compounds with greater activity, a series of racemic alantrypinone derivatives were systematically synthesized using hetero Diels-Alder reactions, and a total of 34 compounds were examined for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate, a high-affinity non-competitive antagonist, to housefly-head membranes. The assay results showed that (1) there is no significant difference between the potencies of natural (+)-alantrypinone and its synthetic racemate; (2) the amide NHs at the 2- and 18-positions are important for high activity; (3) there is a considerable drop in potency for compounds without an aromatic ring at the 16-position; and (4) a large substituent at the 3-position is detrimental to high activity.
Watanabe
Takayuki
T
Graduate School of Pharmaceutical Sciences, Chiba University, Inage-ku, Chiba 263-8522, Japan.
Arisawa
Mitsuhiro
M
Narusuye
Kenji
K
Alam
Mohommad Sayed
MS
Yamamoto
Kazumi
K
Mitomi
Masaaki
M
Ozoe
Yoshihisa
Y
Nishida
Atsushi
A
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D018756:GABA Antagonists / Q000138:chemical synthesis*; D006793:Houseflies; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007306:Insecticides / Q000138:chemical synthesis* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects; D013329:Structure-Activity Relationship
D000470:Alkaloids; D018756:GABA Antagonists; D007211:Indoles; D007306:Insecticides; D011799:Quinazolines; D018079:Receptors, GABA; C115545:alantrypinone