Tetronothiodin, a novel CCKB receptor ligand, antagonizes cholecystokinin-induced Ca2+ mobilization in a pituitary cell line.
We found a novel nonpeptide CCKB receptor antagonist, tetronothiodin (Ro 09-1468), in the culture broth of Streptomyces sp. NR0489. The structure of the compound (C31O8H38S), which has a 19-membered ring with an alpha-acyltetronic acid and tetrahydrothiophene moiety, is completely different from that of any known CCK receptor antagonist. Tetronothiodin inhibited [125I]CCK-8 binding to rat brain CCKB receptors with an IC50 of 3.6 nM, whereas it showed only weak affinity for rat CCKA receptors (IC50 = 70 microM). As demonstrated autoradiographically, tetronothiodin concentration dependently inhibited [125I]CCK-8 binding to CCKB receptors in rat forebrain slices. The effects of tetronothiodin on cytosolic Ca2+ concentrations in GH3 cells, a rat anterior pituitary tumor cell line, were investigated with the fura-2 method. Tetronothiodin inhibited CCK-8-induced Ca2+ mobilization without affecting basal cytosolic Ca2+ concentrations. In conclusion, tetronothiodin is a new, potent and highly selective CCKB receptor antagonist. It is a useful tool for investigating the pharmacological and physiological roles of CCKB receptors.
Kuwahara
T
T
Department of Chemotherapy and Biochemistry, Nippon Roche Research Center, Kamakura, Japan.
Kudoh
T
T
Nagase
H
H
Takamiya
M
M
Nakano
A
A
Ohtsuka
T
T
Yoshizaki
H
H
Arisawa
M
M
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D005663:Furans / Q000494:pharmacology*; D008297:Male; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000187:drug effects*; D012844:Sincalide / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D005663:Furans; D011949:Receptors, Cholecystokinin; D013876:Thiophenes; C073565:tetronothiodin; D002766:Cholecystokinin; D012844:Sincalide; D002118:Calcium