Introduction

Nuclear hormone receptors (NHRs) as members of the nuclear receptor (NR) gene family that regulate a wide range of physiological and pathophysiological effects, are activated through binding of small ligands (hormones), and acting as transcription factors by interaction with distinct DNA motifs on gene promoter to control target gene transcription. Because this mechanism is similar in all tissues it was highly interesting to discover that specific ligands have selective effects on target genes and target tissues, opening up the concept of creating selective NHR modulators for particular therapeutic endpoints. A group of compounds were described that function as estrogen receptor (ER) agonists in some tissues (e.g. bone) but have opposite estrogen action in others (e.g. breast), establishing the concept of selective estrogen receptor modulators (SERMs) and are already available as drugs (Cosman and Lindsay 1999). From the molecular mode of action on the nuclear receptor, SERMs are characterised as mixed agonists/antagonists as measurable in cell culture using reporter gene assays in the absence or presence of the ligand. This mixed behaviour in cell culture is reflected by their in vivo action, and both, agonistic and antagonistic properties may be combined in selected target organs (Katzenellenbogen and Katzenellenbogen 2002). In the agonistic conformation as shown in LBD crystal structure of ERα in complex with estradiol (E2), the helix-12 is in the ligand binding pocket in complex with the agonist, but displaced in the antagonist complex with raloxifen (Brzozowski et al. 1997).