Divergent Nine-Step Syntheses of Perhydrohistrionicotoxin Analogs and Their Inhibition Activity Toward Chicken α4β2-Neuronal Nicotinic Acetylcholine Receptors.

Keisuke Nishikawa, Yosuke Ono, Sumito Mori, Koichi Takayama, Makoto Ihara, Kazuhiko Matsuda, Yoshiki Morimoto

The Journal of organic chemistry 2024 Mar 15

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Histrionicotoxin (HTX) alkaloids, which are isolated from Colombian poison dart frogs, are analgesic neurotoxins that modulate nicotinic acetylcholine receptors (nAChRs) as antagonists. Perhydrohistrionicotoxin (pHTX) is the potent synthetic analogue of HTX and possesses a 1-azaspiro[5.5]undecane skeleton common to the HTX family. Here, we show for the first time the divergent nine-step synthesis of pHTX and its three stereoisomers from the known aldehyde through a one-step construction of the 1-azaspiro[5.5]undecane framework from a linear amino ynone substrate. Surprisingly, some pHTX diastereomers exhibited antagonistic activities on the chicken α4β2-neuronal nAChRs that were more potent than pHTX.

Citation

Keisuke Nishikawa, Yosuke Ono, Sumito Mori, Koichi Takayama, Makoto Ihara, Kazuhiko Matsuda, Yoshiki Morimoto. Divergent Nine-Step Syntheses of Perhydrohistrionicotoxin Analogs and Their Inhibition Activity Toward Chicken α4β2-Neuronal Nicotinic Acetylcholine Receptors. The Journal of organic chemistry. 2024 Mar 15;89(6):4128-4133