Z-Bisdehydrodoisynolic acid [(+/-)-Z-BDDA], an estrogenic carboxylic acid, is highly active in vivo yet binds poorly to estrogen receptors (ERs). Studies of Z-BDDA and its enantiomers demonstrate therapeutic potential as selective ER modulators; however, the activity vs. binding paradox has remained. One possible explanation is that the carboxylic acid group of Z-BDDA may be modified in vivo to an ester or amide. Synthesis of these derivatives showed the relative binding affinity (RBA) of the methyl ester for ERalpha and ERbeta was increased approximately 14- and 20-fold, respectively, relative to the parent compound. Yet, this increased affinity did not result in increased reporter gene expression. In contrast, the amide showed an unexpected approximately 4-fold decrease in RBA to both ERs compared with the parent. The relationship among the RBAs of ester, acid, and amide is consistent with their predicted polarity, suggesting the carboxylic acid, and not the carboxylate of BDDA, binds to ERs. Studies at pH 6.5, 7.4, and 8.0 were consistent with a simple acid-base equilibrium model, with BDDA binding as the undissociated acid and with affinity equal to or exceeding that of estradiol, consistent with high in vivo potency. Furthermore, the alcohol BDD-OH also demonstrated high affinity and increased activity in gene expression assays. In addition to suggesting a resolution to the decades-old binding/activity paradox, these studies may provide a direction for definitive in vivo metabolic and pharmacokinetic studies and provide additional insight into the chemical and metabolic determinants of BBDA's unique tissue selectivity and selective ER modulator activities.