Tetronothiodin

Tetronothiodin (1) is a potent and selective cholecystokinin type B (CCK-B) receptor antagonist produced by Streptomyces sp. NR0489. Its structure was elucidated to be a macrocyclic compound comprising cyclohexene, alpha-acyltetronic acid and tetrahydrothiophene moieties based on various 2D NMR experiments on 1 and its dihydro derivative. The stereochemistries for the cyclohexene and tetrahydrothiophene rings were elucidated based on the analysis of NOEs obtained by NOESY experiments and NOE difference spectroscopy. The relative configuration of the cyclohexene moiety in 1 was revealed to be the same as that of the corresponding part in kijanimicin and chlorothricin, which can be structurally related to 1 in terms of their containing a cyclohexene ring with a spirotetronic acid in the molecule.

Cholecystokinin (CCK) and the structurally related peptide, gastrin, have numerous effects on tissues in the central nervous system and gastrointestinal tract. Recent studies show these effect are mediated by a CCKA and CCKB receptor. Knowledge of the physiological role and role of CCKB receptors in pathologic processes has been particularly limited by the availability of selective, potent receptor antagonists. Recently, new members of five different classes of non-peptide CCKB receptor antagonists are reported and are reviewed briefly. these include compounds isolated from Streptomyces (tetronothiodin, virginiamycin analogues), ureido-acetamide analogues (RP 69758, RP 72540, RP 73870), newer benzodiazepine analogues (L-368,935, L-740,093, YM022), pyrazolidimine analogues (LY 262,691) and glutamic acid analogues (CR2194). Many of these compounds have greater than 1000-fold selectivity for the CCKB over the CCKA receptor and some have greater than 10,000-fold selectivity. The pharmacology and effects of CCKB receptor antagonists on gastric acid secretion is briefly reviewed. Furthermore, the possible clinical usefulness of CCKB receptor antagonists in treating disorders of gastric acid secretion, in inhibiting the trophic effects of gastrin and in other clinical conditions is briefly discussed.

A novel cholecystokinin type-B receptor antagonist named tetronothiodin has been isolated by column chromatography and preparative HPLC from 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 3.6 nM, whereas it did not inhibit CCK8 binding to rat pancreatic membranes (CCK type-A receptors). It also inhibited CCK8 induced Ca2+ mobilization in GH3 cells, a rat anterior pituitary cell line, but was without effect on the basal cytosolic Ca2+ concentration. This finding indicated tetronothiodin was an antagonist of CCK type-B receptors.