• NMDA;
  • schizophrenia;
  • amino acid transporter;
  • glutamate;
  • cognition;
  • D-serine


Thumbnail image of graphical abstract

NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co-agonists, glycine or D-serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D-serine have shown positive results, although concerns over toxicity related to the high-doses required for efficacy remain. Synaptic concentrations of D-serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter-1 (asc-1). Inhibition of asc-1 would increase synaptic D-serine and possibly glycine, eliminating the need for high-dose systemic D-serine or glycine treatment. In this manuscript, we characterize Compound 1 (BMS-466442), the first known small molecule inhibitor of asc-1. Compound 1 selectively inhibited asc-1 mediated D-serine uptake with nanomolar potency in multiple cellular systems. Moreover, Compound 1 inhibited asc-1 but was not a competitive substrate for this transporter. Compound 1 is the first reported selective inhibitor of the asc-1 transporter and may provide a new path for the development of asc-1 inhibitors for the treatment of schizophrenia.

Enhancing NMDA function by increasing synaptic D-serine is a proposed therapeutic approach for the treatment of schizophrenia. Synaptic D-serine levels are regulated by the alanine, serine, cysteine transporter 1 (asc-1). The following study describes the first novel asc-1 inhibitor, Compound 1 (BMS-466442), and provides a path forward for the development of additional asc-1 inhibitors.