title: Homologs of idoxifene: variation of estrogen receptor binding and calmodulin antagonism with chain length.
abstract: A series of homologs of idoxifene [1a, (E)-1-[4-(N-pyrrolidinoethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene ] and selected homologs of 4-iodotamoxifen [2a,(E)-1-[4-(N-dimethylamino)-ethoxy]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 been synthesized and tested for antagonism of of the calmodulin-dependent activity of cAMP phosphodiesterase and for binding affinity to rat uterine estrogen receptor. Compared with 1a (IC(50) =1.5 microM), the homologs showed a progressive increase in calmodulin antagonism with a maximum inhibition at n=7-9 (1f-h)(IC(50)=0.2 microM), declining at n=10 (1i) to IC(50) =1.6 microM. In the pyrrolidino series, estrogen receptor binding affinity peaked at n=3 (1b, RBA= 23; estradiol = 100), declining 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 antagonism.
authors.affiliation: CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Surrey, UK.
authors.forename: I R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: M G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: R M
authors.initials: RM
authors.lastname: Grimshaw
authors.forename: J
authors.initials: J
authors.lastname: Houghton
authors.forename: M
authors.initials: M
authors.lastname: Jarman
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D003600:Cytosol / Q000378:metabolism; D004054:Diethylstilbestrol / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014599:Uterus / Q000378:metabolism
chemical_list: D002147:Calmodulin; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C071362:idoxifene; D004958:Estradiol; D004054:Diethylstilbestrol; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1