Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity

Abstract

Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24­(S)-hydroxycholesterol (24­(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24­(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…The actions of endogenous neurosteroids (Section VIII. Endogenous Allosteric Regulation) stimulated synthetic work on the steroid backbone as a scaffold from which to design potential therapeutic agents (Vales et al, 2012;Ishikawa et al, 2018;La et al, 2019). Substantial information exists about several classes of compounds, including analogs of 24(S)-HC, which are more potent than the endogenous PS and have different structural determinants that include the TMD and connecting linkers (Paul et al, 2013;Wilding et al, 2016).…”

“…Substantial information exists about several classes of compounds, including analogs of 24(S)-HC, which are more potent than the endogenous PS and have different structural determinants that include the TMD and connecting linkers (Paul et al, 2013;Wilding et al, 2016). The 24(S)-HC analogs SGE-201 and SGE-301 (Table 12) enhance open probability and are more potent and efficacious PAMs than 24(S)-HC at all NMDA receptors, with nM potency for SGE-201 at native NMDA receptors (Paul et al, 2013;La et al, 2019). The endogenous 24(S)-HC modulates neuronal function but does not saturate its binding site on NMDA receptors (Sun et al, 2016).…”

Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

“…CYP46A1 KO mice display a decreased NMDAR activity compared to their wild-type littermates (Sun et al 2016a). On the other hand, perfusion of 24(S)-HC or its derivatives SGE-201 and SGE-301 increases STP and LTP in slices from aged rats (Paul et al 2013;La et al 2019) and reverses STP and LTP impairment in slices treated with ketamine (Paul et al 2013). These ex vivo studies suggest that 24(S)-HC acts as an endogenous allosteric modulator of NMDARs and that oxysterols may be used to restore proper NMDAR activity in conditions associated with NMDAR hypofunction.…”

Impact of Allosteric Modulation in Drug Discovery: Innovation in Emerging Chemical Modalities

“…Other recent reports in this area include Sage Therapeutics' NMDA (N-methyl-D-aspartate receptor) PAM SGE-301 25 (20) and Amgen's AM-3607 (21), an allosteric glycine receptor potentiator 26 (Figure 5).…”