Estrogen receptor-beta potency-selective ligands: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues

Through an effort to develop novel ligands that have subtype selectivity fo r the estrogen receptors alpha (ER alpha) and beta (ER beta), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on bot h ER subtypes, but has a 70-fold higher relative binding affinity and 170-f old higher relative potency in transcription assays with ER beta than with ER alpha. To investigate the ER beta affinity- and potency-selective charac ter of this DPN further, we prepared a series of DPN analogues in which bot h the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and n itrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions , to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity f or ER beta (i.e., they are ER beta affinity-selective), and many, but not a ll of them, are also more potent in activating transcription through ER bet a than through ER alpha (i.e., they are ER beta potency-selective). meso-2, 3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succino nitrile are among the, highest ER beta affinity-selective ligands, and they have an ER beta potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower sele ctivities than their nitrile counterparts. The polar analogues have lower a ffinities, and only the fluorinated polar analogues have substantial affini ty selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ER beta selectivity because it provide s the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group beta to the nitrile in DPN or the addit ion of a methyl substitutent at an ortho position on the beta -aromatic rin g increases the affinity and selectivity of these compounds for ER beta. Th ese ER beta -selective compounds may prove to be valuable tools in understa nding the differences in structure and biological function of ER alpha and ER beta.