Novel ligands balance estrogen receptor β and α agonism for safe and effective suppression of the vasomotor response in the ovariectomized female rat model of menopause.
Vasomotor thermo-dysregulation (hot flashes) are an often debilitating symptom of menopause. Effective treatment is achieved primarily through activation of the estrogen receptor (ER)α with estrogens but is also associated with increased risk for breast and uterine cancer. In this study, we have tested novel compounds lacking the B ring of 17-hydroxy-β-estradiol (E2) (A-CD compounds) with differing ratios of ERα:ERβ binding affinities for the ability to reduce diurnal/nocturnal tail-skin temperatures (TSTs) in the ovariectomized female rat menopausal hot flash model. Normal mammary tissue expresses the predominantly antiproliferative ERβ. Therefore, we hypothesized that a preferential ERβ agonist with fractional ERα activity would safely reduce TSTs. The A-CD compound, L17, is a preferential ERβ agonist that has a ratio of ERβ:ERα binding affinity relative to E2 of 9.3 (where ERβ:ERα for E2, 1.0). In the ovariectomized rat, daily administration of low doses (1 mg/kg) of the A-CD compound TD81 (ERα:ERβ relative affinity, 15.2) was ineffective in temperature regulation, whereas L17 showed a trend toward TST reduction. Both E2 and the A-CD compound, TD3 (ERβ:ERα relative affinity, 5.0), also reduced TSTs but had marked proliferative effects on mammary and uterine tissues. At 2 mg/kg, L17 strongly reduced TSTs even more effectively than E2 but, importantly, had only minimal effect on uterine weight and mammary tissues. Both E2- and L17-treated rats showed similar weight reduction over the treatment period. E2 is rapidly metabolized to highly reactive quinones, and we show that L17 has 2-fold greater metabolic stability than E2. Finally, L17 and E2 similarly mediated induction of c-fos expression in neurons within the rat thermoregulatory hypothalamic median preoptic nucleus. Thus, the A-CD compound, L17, may represent a safe and effective approach to the treatment of menopausal hot flashes.
Department of Cellular and Molecular Medicine (C.M., A.S., S.C.R., D.La., M.A.C.P.), and University of Ottawa Neuroscience Institute (D.La.), University of Ottawa, Ottawa, Ontario, Canada K1H 8M5; Centre for Drug Research and Development (D.Le., M.W.), Vancouver, British Columbia, Canada V6T 1Z3; Department of Chemistry (T.D.), University of Ottawa, Ottawa, Ontario, Canada K1N 6N5; and Department of Chemistry (J.S.W.), Carleton University, Ottawa, Ontario, K1S 5B6 Canada.
Chelsea
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McGregor
Andrea
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Sau
Samantha C
SC
Ruddy
Dan
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Leung
Murray
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Webb
Tony
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Durst
James S
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Wright
Diane
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Lagace
M A Christine
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Pratt
D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D019584:Hot Flashes / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D042361:Mammary Glands, Human / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008593:Menopause; D023421:Models, Animal; D015394:Molecular Structure; D010052:Ovariectomy; D011301:Preoptic Area / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology*; D015430:Weight Gain / Q000187:drug effects
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D016760:Proto-Oncogene Proteins c-fos; D004958:Estradiol