Effect of bromolevamisole and other imidazo [2,1-b] thiazole derivatives on adenylate cyclase activity.
We studied the effect of bromolevamisole (BL) and other imidazo [2,1-b] thiazole derivatives--bromodexamisole (BD) and levamisole (LV)--on adenylate cyclase (AC) activity. BL and BD both inhibited forskolin-activated human thyroid AC, while LV had no effect. This inhibition was non-stereospecific and the IC50 values, as measured with 1 mM ATP and 40 microM forskolin, were 0.95 and 0.80 mM for BL and BD, respectively. In contrast, human thyroid alkaline phosphatase (ALP) inhibition was stereospecific, with IC50 values of 0.0012 mM for BL and 0.9 mM for BD. LV was a 10-fold weaker inhibitor of ALP than BL. These results show that ALP inhibition is not correlated with forskolin-activated AC inhibition. Furthermore, in the presence of a competitive inhibitor of GTP (0.1 mM guanosine 5'-O-(2-thiodiphosphate), BL retained its antagonizing effect on forskolin-activated AC which suggests a direct action on the catalytic subunit. The inhibition was of the mixed type, indicating a complex interaction between BL and AC. Glucagon-activated AC activity in rat liver membranes was also inhibited by BL, although to a slightly lesser degree than thyroid stimulating hormone (TSH)-activated AC from human thyroid for a given BL concentration. In cultured human thyroid cells, BL (0.25 mM) induced a potent decrease in cAMP accumulation after 2 hr of stimulation by TSH. Taken together, these results show that BL inhibits AC and that this inhibition is not organ-specific.
Metaye
T
T
Groupe de Recherche en Endocrinologie Experimentale et Clinique (GREEC), CHRU La Miletrie, Poitiers, France.
Millet
C
C
Kraimps
J L
JL
Saunier
B
B
Barbier
J
J
Begon
F
F
D000067956:Adenylyl Cyclase Inhibitors; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D007978:Levamisole / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013773:Tetramisole / Q000031:analogs & derivatives* / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects / Q000201:enzymology
D000067956:Adenylyl Cyclase Inhibitors; D005576:Colforsin; D007978:Levamisole; C006226:4-bromotetramisole; D013773:Tetramisole; D000242:Cyclic AMP; D000469:Alkaline Phosphatase