SAGE-718: A First-in-Class N-Methyl-d-Aspartate Receptor Positive Allosteric Modulator for the Potential Treatment of Cognitive Impairment.

N-Methyl-d-aspartate receptor (NMDAR) positive allosteric modulators (PAMs) have received increased interest as a powerful mechanism of action to provide relief as therapies for CNS disorders. Sage Therapeutics has previously published the discovery of endogenous neuroactive steroid 24(S)-hydroxycholesterol as an NMDAR PAM. In this article, we detail the discovery of development candidate SAGE-718 (5), a potent and high intrinsic activity NMDAR PAM with an optimized pharmacokinetic profile for oral dosing. Compound 5 has completed phase 1 single ascending dose and multiple ascending dose clinical trials and is currently undergoing phase 2 clinical trials for treatment of cognitive impairment in Huntington's disease.

Stimulus-specific adaptation in auditory cortex is an NMDA-independent process distinct from the sensory novelty encoded by the mismatch negativity.

The significance of the mismatch negativity (MMN), an event-related potential measured in humans which indexes novelty in the auditory environment, has motivated a search for a cellular correlate of this process. A leading candidate is stimulus-specific adaptation (SSA) in auditory cortex units, which shares several characteristics with the MMN. Whether auditory cortex responses encode sensory novelty, a defining property of the MMN, however, has not been resolved. To evaluate this key issue, we used several variations of the auditory oddball paradigm from the human literature and examined psychophysical and pharmacological properties of multiunit activity in the auditory cortex of awake rodents. We found converging evidence dissociating SSA from sensory novelty and the MMN. First, during an oddball paradigm with frequency deviants, neuronal responses showed clear SSA but failed to encode novelty in a manner analogous to the human MMN. Second, oddball paradigms using intensity or duration deviants revealed a pattern of unit responses that showed sensory adaptation, but again without any measurable novelty correlates aligning to the human MMN. Finally NMDA antagonists, which are known to disrupt the MMN, suppressed the magnitude of multiunit responses in a nonspecific manner, leaving the process of SSA intact. Together, our results suggest that auditory novelty detection as indexed by the MMN is dissociable from SSA at the level of activity encoded by auditory cortex neurons. Further, the NMDA sensitivity reported for the MMN, which models the disruption of MMN observed in schizophrenia, may occur at a mechanistic locus outside of SSA.