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

Abstract

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.

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators

“…This may reflect that the binding site of CIQ appears to involve GluN2 M1/pre-M1 residues that are more closely associated with GluN1's M4 than with GluN2's M4 [37]. This is consistent with the identification of residues at the extracellular end of GluN1's M4 that affect CIQ activity [37] and UBP684 PAM activity [13].…”

“…Thus, M4 is well positioned for transmitting intracellular signals from the CTD to modulate channel properties. As well-defined for some AMPA receptor NAMs [57], some NMDAR allosteric modulators are known to bind to, or require for their activity, residues in the pre-M1, M1 or M4 helices, for review see [13]. Other modulators such as spermine, PYD-106, PS, GNE-8324 may affect the M1/M4 peripheral ring via the S1/M1 or S2/M4 linkers.…”

“…Recently, several new classes of NMDAR allosteric modulators have been developed with new potential therapeutic applications. Relative to previously available pharmacological agents, these new compounds offer multiple advantages for therapeutic use, for reviews see [13][14][15][16]. For example, a NMDAR PAM, unlike an agonist, could enhance weak NMDAR signals in pathological conditions of NMDAR hypofunction without causing activation of other NMDARs that should stay inactive.…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…As NMDAr antagonists have little success in controlling activity, there is a need for the development of new compounds that modify the activity of this receptor. The fact that there are several subunits that make up NMDAr allows the development of highly specific substances …”

“…[147] As NMDAra ntagonists have little success in controlling activity, there is an eed for the development of new compounds that modify the activity of this receptor.T he fact that there are several subunits that make up NMDAr allows the development of highly specific substances. [150] Several classes of PAMs of NMDAr have been discovered and characterized in the last few years. PAMs present different degrees of channelp erformanceb esides showing differences in bindings ites and selectivity in the subunits.…”