A novel cholecystokinin type-B receptor antagonist named tetronothiodin has been isolated by column chromatography and preparative HPLCfrom the fermentation broth of Streptomyces sp. NR0489. Tetronothiodin inhibited the binding of CCK8(C-terminal octapeptide of cholecystokinin) to rat cerebral cortex membranes (CCK type-B receptors) with an IC50 of 3.6nM, whereas it did not inhibit CCK8binding to rat pancreatic membranes (CCK type-A receptors). It also inhibited CCK8induced Ca2+ mobilization in GH3cells, a rat anterior pituitary cell line, but was without effect on the basal cytosolic Ca2+ concentration. This finding indicated tetronothiodin was an antagonist of CCKtype-B receptors. Cholecystokinin(CCK) is a hormonal regulator of pancreatic secretion1* as well as gallbladder contraction2* and gut motility3). It has also been proposed to act as a neurotransmitter in the central nervous system4*. CCKtype-B (CCK-B)receptors are suggested to be related to appetite5*, pain6'7* and anxiety8'9*. SomeCCK-Breceptor antagonists increased food intake5*, enhanced morphine analgesia6'7* and reduced anxiety8'9* in rats. However, physiological and pharmacological roles of CCK-Breceptorsare not yet fully understood in part because of the shortage of potent and specific CCK-B receptor antagonists. To obtain structurallv unique and specific CCK-Breceptor antagonists, we screened microbial metabolites by employing a binding assay method in which rat cerebral cortex membranesand 125I labeled Bolton-Hunter CCK8 ([125I]-CCK8) were used as the receptors and the radioligand, respectively. In this screening program, we discovered a novel CCK-B receptor antagonist named tetronothiodin (1) from the culture broth of Streptomyces sp. NR0489, and determined the structure to be a macrocyclic compound containing an aacyltetronic acid and a tetrahydrothiophene ring (Fig. 1). A preliminary communication of this work Fie. 1. Structure of tetronothiodin (1

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