In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter -1 (SLC7A10)
Article first published online: 10 DEC 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 129, Issue 2, pages 275–283, April 2014
How to Cite
J. Neurochem. (2014) 129, 275–283.
- Issue published online: 4 APR 2014
- Article first published online: 10 DEC 2013
- Accepted manuscript online: 24 NOV 2013 11:09PM EST
- Manuscript Accepted: 19 NOV 2013
- Manuscript Revised: 18 NOV 2013
- Manuscript Received: 9 SEP 2013
- Bristol-Myers Squibb Research Laboratories Wallingford, CT
- amino acid transporter;
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.