N-methyl-D-aspartate (NMDA) receptors belong to a class of ionotropic glutamate receptors and mediate a slow, Ca2+-permeable component of excitatory synaptic transmission. These receptors are important for a number of normal neurophysiological processes, and the dysfunction of these receptors has been indicated in a variety of neurological disorders. For this reason, identification of new pharmacological and therapeutic probes that selectively potentiate specific subunits of this receptor could be of therapeutic relevance and could help to elucidate important neurobiological principles. We have extended the structure-activity relationship for a tetrahydroisoquinoline class of compounds that includes the prototype CIQ. Modification of specific functionalities yielded compounds that not only potentiate the GluN2C and GluN2D subunits, but also GluN2B. In rare cases there appears to be modest potentiation of NMDA receptors that contain the GluN2A subunit. We have also separated the enantiomers for a potent compound in the series, and found that the S-(-) enantiomer is active at GluN2B, GluN2C, and GluN2D subunits, while the R-(+) enantiomer is GluN2C and GluN2D subunit selective. While initial molecules synthesized in the CIQ class of compounds were selective only for the GluN2C and GluN2D-containing receptors, we show here that the modification of certain features of the scaffold can tune this series to target other GluN2 subunits.

Structure activity relationship of tetrahydroisoquinoline N-methyl-D-aspartate receptor positive allosteric modulators can be modified to target GluN2B-containing receptors

249th National Meeting (2015)

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