Investigations on the Effects of Basic Side Chains on the Hormonal Profile of (4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines

Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-ylethane, or a pyrrolidin-1-ylethane side chain into one of the 4-hydroxyphenyl rings. The compounds were tested for agonistic and antagonistic activity on hormone sensitive, ERα-positive MCF7-2a cells, stably transfected with the plasmid EREwtcluc and on U-2 OS cells transiently transfected with plasmids encoding for ERα (pSG5-ERα) or ERβ (pSG5-ERβ FL) as well as the reporter plasmid (ERE)2luc+. Despite the presence of a basic side chain, the majority of the 4,5-diaryl-2-imidazolines showed agonistic effects. The most active compound, (4R,5S)/(4S,5R)-4-(2-chloro-4-(2-piperidin-1-ylethoxy)phenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline (5a), achieved at ERα an EC50 value of 0.085 μM and at ERβ an EC50 = 0.40 μM. High antagonistic properties only possessed the C2 ethyl substituted compounds 2a and 4a. (4R,5S)/(4S,5R)-2-Ethyl-4-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-ylethoxy)phenyl)-2-imidazoline (2a) reduced the effect of estradiol at ERα strongly with IC50 = 0.038 μM, while its antagonistic properties at ERβ were distinctly lower (IC50 = 9.00 μM), probably due to the partial agonistic effects (EC50 = 0.50 μM).