Evidence that tamoxifen binds to calmodulin in a conformation different to that when binding to estrogen receptors, through structure-activity study on ring-fused analogues.
A ring-fused analogue of tamoxifen, which had previously been shown to have practically identical estrogen receptor (ER) affinity and antitumour potency against estrogen responsive cells as tamoxifen, failed to inhibit calmodulin-dependent cyclic AMP phosphodiesterase. The substitution of an extra methyl group into the ring-fused analogue, at a position which the ethyl group of tamoxifen can occupy in one of its conformations, restored the calmodulin inhibition. Also, the replacement of the tamoxifen ethyl group by methyl diminishes calmodulin inhibition. Direct interaction of these tamoxifen analogues with calmodulin was demonstrated through the use of the fluorescent probe, 2-p-toluidinyl-naphthalene-6-sulfonic acid (TNS). These findings lead to the conclusion that tamoxifen binds to calmodulin in a conformation not accessible to the fused analogue and therefore likely to be different to that which binds to the ER. Also, the results on the ring-fused analogues indicate that the calmodulin binding cannot be essential for antitumour activity.
McCague
R
R
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.
Rowlands
M G
MG
Grimshaw
R
R
Jarman
M
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000242:Cyclic AMP / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D005456:Fluorescent Dyes; D008968:Molecular Conformation; D009282:Naphthalenesulfonates; D011960:Receptors, Estrogen / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*
D002147:Calmodulin; D005456:Fluorescent Dyes; D009282:Naphthalenesulfonates; D011960:Receptors, Estrogen; D013449:Sulfonamides; D013629:Tamoxifen; C017967:W 7; C009497:2-(4-toluidino)-6-naphthalenesulfonic acid; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1