A novel Na+‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine

NMDA receptor dysfunctions are hypothesized to underlie the pathophysiology of schizophrenia, and treatment with D‐serine (D‐Ser), an NMDA receptor coagonist, may improve the clinical symptoms of schizophrenia. Thus, upregulating the synaptic D‐Ser level is a novel strategy for schizophrenia treatment. Na⁺‐independent alanine‐serine‐cysteine transporter 1 (asc‐1) is a transporter responsible for regulating the extracellular D‐Ser levels in the brain. In this study, we discovered a novel asc‐1 inhibitor, (+)‐amino(1‐(3,5‐dichlorophenyl)‐3,5‐dimethyl‐1H‐pyrazol‐4‐yl)acetic acid (ACPP), and assessed its pharmacological profile. ACPP inhibited the D‐[³H]Ser uptake in human asc‐1‐expressing CHO cells and rat primary neurons with IC₅₀ values of 0.72 ± 0.13 and 0.89 ± 0.30 μM, respectively. In accordance with the lower asc‐1 expression levels in astrocytes, ACPP did not inhibit D‐Ser uptake in rat primary astrocytes. In a microdialysis study, ACPP dose dependently decreased the extracellular D‐Ser levels in the rat hippocampus under the same conditions in which the asc‐1 inhibitor S‐methyl‐L‐cysteine (SMLC) increased it. To obtain insights into this difference, we conducted a D‐[³H]Ser efflux assay using asc‐1‐expressing CHO cells. ACPP inhibited D‐[³H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc‐1. © 2016 Wiley Periodicals, Inc.