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Review
. 2022 Jan;600(2):233-259.
doi: 10.1113/JP280875. Epub 2021 Aug 17.

Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

Chloé Geoffroy  1 , Pierre Paoletti  1 , Laetitia Mony  1
Affiliations
Free article
Review

Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

Chloé Geoffroy et al. J Physiol. 2022 Jan.
Free article

Abstract

NMDA receptors (NMDARs) are glutamate-gated ion channels that play key roles in synaptic transmission and plasticity. Both hyper- and hypo-activation of NMDARs are deleterious to neuronal function. In particular, NMDAR hypofunction is involved in a wide range of neurological and psychiatric conditions like schizophrenia, intellectual disability, age-dependent cognitive decline, or Alzheimer's disease. While early medicinal chemistry efforts were mostly focused on the development of NMDAR antagonists, the last 10 years have seen a boom in the development of NMDAR positive allosteric modulators (PAMs). Here we review the currently developed NMDAR PAMs, their pharmacological profiles and mechanisms of action, as well as their physiological effects in healthy animals and animal models of NMDAR hypofunction. In light of the complexity of physiological outcomes of NMDAR PAMs in vivo, we discuss the remaining challenges and questions that need to be addressed to better grasp and predict the therapeutic potential of NMDAR positive allosteric modulation.

Keywords: NMDA; PAM; allosteric modulation; cognitive enhancement; excitotoxicity; glutamate receptors; ligand-gated ion channels.

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