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-[(3) H]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-[(3) H]Ser efflux assay using asc-1-expressing CHO cells. ACPP inhibited D-[(3) H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc-1. © 2016 Wiley Periodicals, Inc.
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
Katsuya
0000-0002-9326-937X
K
Sakimura
Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
Kenji
K
Nakao
Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
Masato
M
Yoshikawa
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
Motohisa
M
Suzuki
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
Haruhide
H
Kimura
D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003038:Cobamides; D003412:Cricetulus; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology; D008297:Male; D017551:Microdialysis; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
D026962:Amino Acid Transport System ASC; D003038:Cobamides; D003510:Cyclohexanes; D015778:Minor Histocompatibility Antigens; D063065:Organophosphonates; C498849:Slc1a5 protein, rat; C583864:Slc7a10 protein, rat; C465815:adenosylcobinamide 2-chlorophenyl phosphate; D012694:Serine; D012964:Sodium; C008425:S-methylcysteine; D003545:Cysteine
D-serine; asc-1 inhibitor; efflux; microdialysis; schizophrenia