NMDA receptors are heterotetrameric ligand-gated ion channels that are involved in fast excitatory transmission and the synaptic plasticity involved in learning and memory. They are comprised of two obligatory GluN1 subunits along with two GluN2 (A–D) or GluN3 (A-B) subunits. Activation of the NMDA receptor is of interest for enhancing cortical plasticity in diseases such as schizophrenia, where cognitive dysfunction is prevalent as well as other potential utility in diseases of glutamate hypofunction. Development of NMDA ligands that bind to the glutamate and/or glycine site has been hampered, however, by lack of clinical efficacy combined with a prevalence of undesirable side effects. Furthermore, direct agonism of the NMDA receptor can be associated with neurotoxic cell death. The glutamate-binding site is remarkably conserved across the GluN2 subunits and so it has proved difficult to develop subunit-selective ligands that target this site. Thus, interest has now turned to the development of ligands that bind to allosteric sites on the NMDA complex in the hope that they will be able to fine-tune receptor function and thus produce efficacious compounds with fewer undesirable adverse events. Sage Therapeutics has recently reported that 24-(S)-hydroxycholesterol, a cholesterol metabolite or sterol, and SGE-301 are potent allosteric modulators of NMDA receptors. SGE-301 is a synthetic sterol that has desirable in vivo drug-like properties and has shown reversal of NMDAR blocker-induced impairment of cognitive and social behavior. This talk will focus on the discovery of a novel series of synthetic sterols as NMDA positive allosteric modulators.

Novel sterols as modulators of the NMDA receptor

251st National Meeting (2016)

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