Potential Clinical Applications of (-), (+) and (±)-Z-Bisdehydrodoisynolic Acids in Metabolic Disorders

Jeremy   E.   Davis; Yuqing      Hou; Cal   Y.   Meyers; William   J.   Banz

Abstract

Doisynolic acids (DAs), such as (±)-Z-bisdehydrodoisynolic acid [(±)-Z-BDDA], are a group of synthetically produced compounds with structural similarity to 17β-estradiol (E2), which exhibit significant estrogenic activity. They regulate estrogen receptor-α and -β (ERα/β) reporter gene activation, as well mediate significant uterotropic effects in vivo. Despite these estrogen-specific effects, (±)-Z-BDDA and related compounds exhibit low ER binding activity in vitro. This may reflect changes in chemical structure or cellular environment necessary for optimum binding of DAs. are possible explanations for the binding/activity paradox. Selective estrogen receptor modulators (SERMs), such as tamoxifen, provide estrogenic activity without undesired adverse effects of E2. The strong SERM activity and limited side effects of (±)-Z-BDDA make it an ideal alternative to hormone replacement therapy. Recent investigation of (±)-Z-BDDA has revealed a marked protection against obesity, diabetes, cardiovascular disease, and prostate cancer. The underlying mechanisms involved in attenuation of these degenerative diseases are not fully elucidated but may relate to the compounds significant estrogenic and anti-inflammatory properties. This review summarizes some of the proposed mechanisms for different therapeutic applications of DAs, including obesity and diabetes, as well as some patents on (±)- Z-BDDA protection against prostate cancer.

Keywords: (+)-Z-bisdehydrodoisynolic acid ((+)-Z-BDDA), insulin resistance, selective estrogen receptor modulator (SERM), metabolic rate, obese Zucker rat (OZR).

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