Similarities and distinctions in the mode of action of different classes of antioestrogens.

Since the description of the first antioestrogen, MER 25, more than four decades ago (Lerner et al. 1958), and of tamoxifen ten years later (Harper droloxifene, Bruning 1992). These molecules have very similar chemical and pharmacological properties: they are all non-steroidal, triphenylethylene-derived structures and all are partial agonists (mixed agonist/antagonist activities). A number of other non-steroidal structures with antioestrogenic activity have been reported, including substituted tetrahydronaphthalenes (e.g. nafoxidene, Duncan et al. 1963; trioxifene, Jones et al. 1979), indole derivatives (e.g. zindoxifene, Stein et al. 1990; ZK 119010, von Angerer 1990), benzothiophenes (e.g. LY117018, Black LY156758 (keoxifene), Clemens et al. 1983) and benzopyrans (Sharma et al. 1990, Grese et al. 1996). All of these antioestrogens share with tamoxifen the pharmacological characteristic of partial-agonist activity; thus, whilst they antagonise the trophic action of oestrogens, this activity is incomplete because each compound has intrinsic oestrogen-like stimulatory (agonist) activity in vivo. The effect of drug treatment is a balance between agonist and antagonist activity. Whilst the term ‘partial-agonist’ accurately conveys the idea that all of these antioestrogens have some oestrogenic activity, it does not adequately describe their complex organ, cell and