Synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. This phenomenon is proposed to be the basis for learning and memory of neuronal networks and has the potential to recover from synaptic loss. Substantial evidence exists correlating synaptic dysfunction/loss with degree of cognitive impairment and late stages of Alzheimer's Disease (AD) for which synaptic plasticity represents a potential therapeutic approach.
NMDA receptors are glutamatergic receptors that can be activated precisely during the coincidence of excitatory synaptic transmission with neuronal activity. This precise activation of the NMDA receptor is key for synaptic plasticity and remodeling neuronal circuits. Each NMDA receptor contains different subunits: two NR1 and two NR2 divided into four subtypes A-D. The NR2B subunit caught our attention.  Its expression is developmentally regulated: a switch in NR2B-containing receptors by NR2A-containing receptors is seen after development which is associated with the closure of the “critical period of synaptic plasticity during brain development”. NR2B re-expression can restore critical period-like plasticity in adult sensory cortex, thus promoting learning and memory. Our aim is to identify PAMs of NR2B function to enhance synaptic plasticity and improve learning and memory in neuronal circuits with synaptic loss such as aged/AD brains.

Here we report the structure activity relationship of a series of NR2B PAMs pyridopyrazoles originated from a HTS campaign. Further characterization of advanced compounds revealed their potential as in vivo tools to understand the role of NR2B in synaptic plasticity and their potential application in neurodegenerative diseases.