Neurosteroid enantiomers as potentially novel neurotherapeutics

Abstract

Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These steroids modulate major signaling systems in the brain and intracellular processes including inflammation, cellular stress and autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which are physiochemically identical to their natural counterparts except for rotation of polarized light. These studies led to insights in how NAS interact with receptors, ion channels and intracellular sites of action. Certain effects of NAS show high enantioselectivity, consistent with actions in chiral environments and likely direct interactions with signaling proteins. Other effects show no enantioselectivity and even reverse enantioselectivity. The spectrum of effects of NAS enantiomers raises the possibility that these agents, once considered only as tools for preclinical studies, have therapeutic potential that complements and in some cases may exceed their natural counterparts. Here we review studies of NAS enantiomers from the perspective of their potential development as novel neurotherapeutics.

Keywords: Allopregnanolone; Calcium channels; GABA(A) receptors; NMDA receptors; Neuroinflammation; Neuroprotection; Pregnanolone; Pregnenolone sulfate.

Fig.1.

Neuroactive steroids in clinical use or development. The eight chiral centers in allopregnanolone (brexanolone) are marked with asterisks. By convention, dashed and solid wedges designate the α and β configurations of substituents at chiral stereocenters. Important structural features described in the text are highlighted in red font.

Fig. 2.

Structures of enantiomeric steroids. Stereocenters are denoted by solid (β configuration) or dashed (α configuration) wedges and are the opposite of the stereocenters in naturally occurring steroids. Comparison of the structures ent-allopregnanolone and naturally occurring allopregnanolone (Fig. 1) shows the opposite configuration of all eight chiral centers.

Fig. 3.

The figure summarizes various effects where the enantiomers of AlloP have been compared, including effects with enantioselectivity (nat > ent), and effects where the enantiomers are equivalent (nat = ent). See text for details and references.

Fig. 4.

Various effects of PREGS and its enantioselectivity are depicted and highlight effects with enantioselectivity (nat > ent), no enantioselectivity (nat = ent) and reverse enantioselectivity (ent > nat). The figure also shows complex effects of the DHEAS enantiomers. See text for details and references.