molecules of the month

Context. SAGE-718 (Sage Therapeutics) is an oral N-methyl-d-aspartate receptor (NMDAR) Positive Allosteric Modulator (PAM) being developed for cognitive impairment in Huntington’s disease. Aberrant NMDAR signaling has been implicated in several neurological and psychiatric disorders, making the receptor an attractive drug target. Although hyperactivation of the receptor has been considered to mediate some cardiovascular and neurodegenerative diseases, its hypofunction has also been associated with diseases such as schizophrenia and Huntington’s disease. Due to toxicity-related issues associated with increasing NDMAR activity through an agonist therapeutic, one alternative indirect therapeutic approach is using PAMs, with another through GlyT1 inhibition (see iclepertin, which we recently featured). SAGE-718 was developed from a brain cholesterol metabolite, 24(S)-hydroxycholesterol [24(S)-HC], which was previously identified as a selective PAM…