Nestorone® (NES) is a highly potent non-androgenic progestin being developed for contraception. NES is a synthetic progestin that may possess neuroprotective and myelin regenerative potential as an added health benefits. In receptor transactivation experiments, NES displayed greater potency than progesterone to transactivate the human progesterone receptor (hPR). This was confirmed by docking experiments which revealed that NES adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone and forms additional stabilizing contacts between 17-acetoxy and 16-methylene groups and PR LBD supporting its higher potency than progesterone. The analogue 13-ethyl NES also establishes similar contacts as NES with Met909, leading to comparable potency as NES. In contrast, NES is not stabilized within the human androgen receptor (hAR)-LBD leading to negligible AR transactivation. Since progesterone acts in the brain by both PR-binding and indirectly via the metabolite allopregnanolone binding to GABAA receptor (GABAAR), we investigated if NES is metabolized to 3, 5-tetrahydronestorone (3, 5-THNES) in the brain and if this metabolite could interact with GABAAR. In female mice, low concentrations of reduced NES metabolites were identified by Gas Chromatography-Mass Spectrometry in both plasma and brain. However, electrophysiological studies showed that 3, 5-THNES exhibited only limited activity to enhance GABAAR-evoked responses with WSS-1 cells and did not modulate synaptic GABAARs of mouse cortical neurons. Thus the inability of reduced metabolite of NES (3, 5-THNES) to activate GABAAR suggests that the neuroprotective and myelin regenerative effects of NES are mediated via PR binding and not via its interaction with the GABAAR.
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Date of publication: 1 November 2016; Endocrinology: Endocrine Society Journal 2016
Author information: Narender Kumar (1); Jerôme Fagart (2); Philippe Liere (3); Scott J. Mitchell (4); Alanah R. Knibb (4); Isabell Petit-Topin (2); Marion Rame (3); Martine El-Etr (3); Michael Schumacher (3); Jeremy J. Lambert (4); Marie-Edith Rafestin-Oblin (2); & Regine Sitruk-Ware (1)
(1) Population Council, Center for Biomedical Research, NY, NY, USA
(2) U773 INSERM, Paris, France
(3) U1195 INSERM, UNiversity Paris Sud, Le Kremlin Bicêtre, France
(4) Division of Neuroscience, Ninewells Hospital & Medical School, Dundee University, Dundee, Scotland, UK