Pharmacological Profile of 6,12-Dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one, a Novel Human Estrogen Receptor Agonist

• Published in: Biological & pharmaceutical bulletin 2002, Vol.25(3), pp.335-341
• Main Authors: Jacquot, Yves, Cleeren, Anny, Laios, Ioanna, Ma, Yan, Boulahdour, Athem, Bermont, Laurent, Refouvelet, Bernard, Adessi, Gérard, Leclercq, Guy, Xicluna, Alain
• Format: Article
• Language: English
• Subjects: benzopyrano[3,4-b][1,4]benzothiazin-6-ones; binding mode; Biological and medical sciences; Cell Line; coumestrol; estrogenicity; Hormones. Endocrine system; Humans; ionic microscopy; Magnetic Resonance Spectroscopy; Medical sciences; MVLN; Pharmacology. Drug treatments; Radioligand Assay; Receptors, Estrogen - agonists; Receptors, Estrogen - metabolism; Recombinant Proteins - agonists; Spectrometry, Mass, Electrospray Ionization; Thiazines - chemistry; Thiazines - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.25.335

Pharmacological studies were carried out to characterize further the endocrinological profile and the binding mode to the estrogen receptor (ER) of 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one (1). Binding experiments were conducted with highly purified recombinant human estrogen receptors hERα and β. Potent estrogenic activity of compound 1 was assessed by testing its ability to down-regulate ERs and to enhance estrogen receptor element (ERE)-dependent transcription. The latest step of our work dealt with the synthesis of the 9-fluorinated derivative 15 for ionic microscopy experiments to determine the intracellular localization of compound 1. Although 1 failed to compete with [3H]E2 for binding to both ER isoforms, evidence was reported that it interacted with hERα in MCF-7 cells (ER down-regulation/ERE-dependent luciferase induction). Hence, an appropriate conformation of the hormone binding domain, most probably conferred by co-regulators of ER, is required for the onset of an activity of the compound 1. Estrogenic activity was weak but on the order of magnitude of that of coumestrol (slightly weaker). The synthesis of the 9-methoxylated derivative 16 and its pharmacological evaluation led us to propose a binding mode of 1 on hERα. Compound 1 appears to interact with ERα mainly through interactions of its 3-methoxy substituent with the residue His-524 of the hormone binding domain.