INHIBITION OF OESTRADIOL BINDING TO OESTROGEN RECEPTOR PROTEINS BY A METHYL-SUBSTITUTED ANALOGUE OF TAMOXIFEN

Abstract

Department of Pharmacology, School of Medicine, Leeds, LS2 9NL (Received 8 December 1975) The introduction of two methyl groups positioned ortho to the side-chain in aryl alkyl ethers is known to alter the pharmacological properties and to limit the possible conformations of the side-chain (Clark & Williams, 1967; Clark, Dawes & Williams, 1968; Coggan, McPhail & Roe, 1969). The anti-oestrogens tamoxifen, clomiphene and nafoxidine all possess β-aminoethoxy side-chains and Lednicer, Lyster & Duncan (1967) demonstrated the importance of side-chain length and its position in space for biological activity. Tamoxifen [trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene], a potent anti-oestrogen in the rat, exhibits oestrogenic activity in the mouse and slight oestrogenic activity may also be demonstrated in the rat at high dose levels (Harper & Walpole, 1966). Furthermore, tamoxifen has been shown to be capable of inhibiting oestradiol binding in the mouse uterus both in vitro (Terenius, 1971; Skidmore, Walpole & Woodburn, 1972; Jordan & Koerner,