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Positive and Negative Allosteric Modulators of N-Methyl- d -aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)3-23
Number of pages21
JournalJournal of Medicinal Chemistry
Issue number1
Early online date5 Mar 2018
DateAccepted/In press - 5 Mar 2018
DateE-pub ahead of print - 5 Mar 2018
DatePublished (current) - 10 Jan 2019


Excitatory activity in the CNS is predominately mediated by l-glutamate through several families of l-glutamate neurotransmitter receptors. Of these, the N-methyl-d-aspartate receptor (NMDAR) family has many critical roles in CNS function and in various neuropathological and psychiatric conditions. Until recently, the types of compounds available to regulate NMDAR function have been quite limited in terms of mechanism of action, subtype selectivity, and biological effect. However, several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity. These new agents act at several newly recognized binding sites on the NMDAR complex and offer significantly greater pharmacological control over NMDAR activity than previously available agents. The purpose of this review is to summarize the structure-activity relationships for these new NMDAR modulator drug classes and to describe the current understanding of their mechanisms of action.

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