title: In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter -1 (SLC7A10).
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.
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brown
authors.forename: Lisa
authors.initials: L
authors.lastname: Hunihan
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Prack
authors.forename: David G
authors.initials: DG
authors.lastname: Harden
authors.forename: Joanne
authors.initials: J
authors.lastname: Bronson
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Dzierba
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gentles
authors.forename: Adam
authors.initials: A
authors.lastname: Hendricson
authors.forename: Rudy
authors.initials: R
authors.lastname: Krause
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Westphal
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D006639:Histidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012694:Serine / Q000378:metabolism; D054852:Small Molecule Libraries; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D000596:Amino Acids; C000588580:BMS-466442; D018690:Excitatory Amino Acid Agonists; D007211:Indoles; D016194:Receptors, N-Methyl-D-Aspartate; C498799:SLC7A10 protein, human; D054852:Small Molecule Libraries; D012694:Serine; D006639:Histidine; D005998:Glycine
keywords: D-serine; NMDA; amino acid transporter; cognition; glutamate; schizophrenia