QSAR of estrogen receptor modulators: exploring selectivity requirements for ERα versus ERβ binding of tetrahydroisoquinoline derivatives using E-state and physicochemical parameters

Considering importance of developing selective estrogen receptor modulators (SERMs), the present paper explores selectivity requirements of tetrahydroisoquinoline derivatives for binding with ERα versus ERβ receptors using E-state index and physicochemical parameters. The best model [n = 21, Q2 = 0.512, , R = 0.819, F = 11.6 (df 3, 17)] for ERα binding data obtained from radioligand binding assay showed importance of C1, C15 and lipophilicity (log P) while the best model [n = 21, Q2 = 0.768, , R = 0.904, F = 40.1 (df 2, 18)] for ERβ binding data showed importance of C1 and molar refractivity (MR). While modeling ERα/ERβ selectivity [n = 21, Q2 = 0.695, , R = 0.882, F = 19.8 (df 3, 17)], C1, C15 and molar refractivity were found to be significant contributors. The data obtained from cellular transcription assay were also modeled. In case of ERα, the best equation involving E-state values of C1 and C14 and log P explained 62.1% of the variance while the best equation for ERβ involving E-state values of C1 and C15 and MR explained 64.6% of the variance of the response variable. In case of ERα/ERβ selectivity, the best equation involving E-state values of O8, C14 and N27 showed 48.3% explained variance, which increased to 63.5% on deletion of single outlier. From the analysis it appears that the nitrogen atom of the aminoethoxyphenyl substituent and 6-hydroxy substituent of the tetrahydroisoquinoline nucleus play important roles for ERα/ERβ selectivity in addition to R1 and R2 substituents.