The
N-methyl-D-aspartate (
NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo- or hyperactivation of
NMDA receptors is critically involved in many neurological and psychiatric conditions, such as
pain,
stroke,
epilepsy, neurodegeneration,
schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of
NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds. We have identified allosteric modulators with several novel patterns of
NMDA receptor subtype selectivity that have a novel mechanism of action. In a series of carboxylated
naphthalene and
phenanthrene derivatives, compounds were identified that selectively potentiate responses at GluN1/GluN2A [e.g., 9-iodophenanthrene-3-carboxylic
acid (UBP512)]; GluN1/GluN2A and GluN1/GluN2B [9-cyclopropylphenanthrene-3-
carboxylic acid (UBP710)]; GluN1/GluN2D [3,5-dihydroxynaphthalene-2-
carboxylic acid (UBP551)]; or GluN1/GluN2C and GluN1/GluN2D receptors [6-, 7-, 8-, and 9-nitro isomers of naphth[1,2-c][1,2,5]
oxadiazole-5-
sulfonic acid (NSC339614)] and have no effect or inhibit responses at the other
NMDA receptors. Selective inhibition was also observed; UBP512 inhibits only GluN1/GluN2C and GluN1/GluN2D receptors, whereas 6-bromo-2-oxo-2H-chromene-3-carboxylic
acid (UBP608) inhibits GluN1/GluN2A receptors with a 23-fold selectivity compared with GluN1/GluN2D receptors. The actions of these compounds were not competitive with the agonists
L-glutamate or
glycine and were not voltage-dependent. Whereas the N-terminal regulatory domain was not necessary for activity of either potentiators or inhibitors, segment 2 of the agonist
ligand-binding domain was important for potentiating activity, whereas subtype-specific inhibitory activity was dependent upon segment 1. In terms of chemical structure, activity profile, and mechanism of action, these modulators represent a new class of pharmacological agents for the study of
NMDA receptor subtype function and provide novel lead compounds for a variety of
neurological disorders.