HOMOLOGS OF IDOXIFENE - VARIATION OF ESTROGEN-RECEPTOR BINDING AND CALMODULIN ANTAGONISM WITH CHAIN-LENGTH

A series of homologs of idoxifene [1a, ethoxy)phenyl]-1-(4-iodophenyl) -2-phenyl-1-butene] and selected homologs of 4-iodotamoxifen [2a, etho xy]phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene] with the side chain (CH 2)(n) varying in length from n = 3 (1b, 2b) to n = 10 (1i, 2i) have be en synthesized and tested for antagonism of the calmodulin-dependent a ctivity of cAMP phosphodiesterase and for binding affinity to rat uter ine estrogen receptor. Compared with 1a (IC50 = 1.5 mu M), the homolog s showed a progressive increase in calmodulin antagonism with a maximu m inhibition at n = 7-9 (1f-h) (IC50 = 0.2 mu M), declining at n = 10 (1i) to IC50 = 1.6 mu M. In the pyrrolidino series, estrogen receptor binding affinity peaked at n = 3 (1b, RBA = 23; estradiol = 100), decl ining by n = 10 (1i) to RBA = 0.4, but the homolog n = 8 (1g, RBA = 3. 5) was still comparable to tamoxifen (RBA = 3.9). A similar pattern of activity was seen for the dimethylamino counterparts. These compounds represent a new class of antiestrogens with potent calmodulin antagon ism.