Zerumbone 1 is an 11-membered cyclic sesquiterpene obtained from the rhizomes of Zingiber zerumbet SMITH (Zingiberaceae). In this study, we investigated the structure–activity relationship of 1 , α-humulene ( 2 ), tetrahydrozerumbone stereoisomers ( 3 – 5 ), and tetrahydrozerumbone derivatives ( 6 – 9 ). The oxygen-containing functional groups and the configurations at C1 and C2 contributed to the spontaneous locomotor activity reduction of zerumbone 1 and derivatives 2 – 9 .