Alantrypinone and its derivatives: Synthesis and antagonist activity toward insect GABA receptors

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• 作者：Takayuki Watanabe ; Mitsuhiro Arisawa ; Kenji Narusuye ; Mohommad Sayed Alam ; Kazumi Yamamoto ; Masaaki Mitomi ; Yoshihisa Ozoe ; Atsushi Nishida
• 关键词：antrypinone ; Insect GABA receptors ; Hetero Diels– ; Alder reaction
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：1 January 2009
• 年：2009
• 卷：17
• 期：1
• 页码：94-110
• 全文大小：622 K

文摘

The γ-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 [³H]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.