<i>N</i>-Methyl-D-Aspartate receptors (NMDARs) are critical to synaptic signaling and plasticity and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer’s disease. This talk will describe the discovery and optimization of two distinct series of NMDAR positive allosteric modulators (PAMs) with a focus on general concepts related to allosterism and ion channel activation. Strategies related to series selection, subtype selectivity, assay development, mechanism of action, structure-based design, and in vivo model selection will also be discussed. Together, an overview of our NMDAR PAM drug discovery program will be provided summarizing lessons that can be broadly applied to other ion channel and/or activator targets.

Strategies and challenges on the GluN2A-selective NMDA PAM program: A perspective on positive allosteric modulator (PAM) drug discovery

255th National Meeting (2018)

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