Neuroactive steroids with perfluorobenzoyl group

During an initial study in searching for the alternative derivatives suitable for photolabeling of neuroactive steroids, perfluorobenzoates and perfluorobenzamides in position 17 of 5β-androstan-3α-ol were synthesized from the corresponding 17-hydroxy and 17-amino derivatives. After transformation into glutamates or sulfates, 17α-epimers had comparable inhibitory activity at NMDA receptors to the natural neurosteroid (20-oxo-5β-pregnan-3β-yl sulfate), however, were more potent (2- to 36-fold) than their 17β-substituted analogs. In one case, fluorine in position 4′ of perfluorobenzoate group was substituted with azide and activity of the final glutamate was retained comparing with the corresponding perfluorobenzoate. The series was expanded with perfluorobenzoyl derivatives of pregnanolone: Perfluorobenzamide of glutamate and perfluorobenzoate of 11α-hydroxy pregnanolone were prepared and tested. From nine tested compounds, four of them exhibit very good inhibition activity and can serve as promising leads for photolabeling experiments.

► New type of neuroactive steroids for photoaffinity labeling were designed. ► Steroid perfluorobenzoates and perfluorobenzamides were synthesized. ► Perfluorobenzoyl analogs of pregnanolone sulfate inhibited NMDA receptor. ► Orientation of perfluorobenzoyl in position 17 influenced inhibition.