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Estrogen Receptor-β Agonist Diarylpropionitrile: Biological Activities of R- and S-Enantiomers on Behavior and Hormonal Response to Stress

Department of Biomedical Sciences (M.J.W., R.J.H.), Neuroscience Division, Colorado State University, Fort Collins, Colorado 80523; and Department of Obstetrics and Gynecology (T.J.W.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

Address all correspondence and requests for reprints to: Robert J. Handa, Department of Basic Medical Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, Arizona 85004. E-mail: rhanda{at}arizona.edu.

Estrogens have been shown to have positive and negative effects on anxiety and depressive-like behaviors, perhaps explained by the existence of two distinct estrogen receptor (ER) systems, ER and ERβ. The ERβ agonist, diarylpropionitrile (DPN) has been shown to have anxiolytic properties in rats. DPN exists as a racemic mixture of two enantiomers, R-DPN and S-DPN. In this study, we compared R-DPN and S-DPN for their in vitro binding affinity, ability to activate transcription in vitro at an estrogen response element, and in vivo endocrine and behavioral responses. In vitro binding studies using recombinant rat ERβ revealed that S-DPN has a severalfold greater relative binding affinity for ERβ than does R-DPN. Furthermore, cotransfection of N-38 immortalized hypothalamic cells with an estrogen response element-luc reporter and ERβ revealed that S-DPN is a potent activator of transcription in vitro, whereas R-DPN is not. Subsequently, we examined anxiety-like behaviors using the open-field test and elevated plus maze or depressive-like behaviors, using the forced swim test. Ovariectomized young adult female Sprague Dawley rats treated with racemic DPN, S-DPN, and the ERβ agonist, WAY-200070, showed significantly decreased anxiety-like behaviors in both the open-field and elevated plus maze and significantly less depressive-like behaviors in the forced swim test compared with vehicle-, R-DPN-, or propylpyrazoletriol (ER agonist)-treated animals. In concordance with the relative binding affinity and transcriptional potency, these results demonstrate that the S-enantiomer is the biologically active form of DPN. These studies also indicate that estrogen’s positive effects on mood, including its anxiolytic and antidepressive actions, are due to its actions at ERβ.

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