The glycine transporter-1 inhibitors NFPS and Org 24461: A pharmacological study

Laszlo G. Harsing, Istvan Gacsalyi, Geza Szabo, Eva Schmidt, Nora Sziray, Claude Sebban, Brigitte Tesolin-Decros, Peter Matyus, Andras Egyed, Michael Spedding, Gyorgy Levay

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The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC50 values of 0.022 and 2.5 μM. Neither NFPS nor Org 24461 (0.1 μM) showed significant binding to α-1, α-2, and β-adrenoceptors, D1 and D2 dopamine receptors, and 5-HT1A and 5-HT2A serotonin receptors in membranes prepared from rat brain or to cloned 5-HT6 and 5-HT7 receptors. At 10 μM concentrations, binding affinity was measured for NFPS to 5-HT2A and 5-HT2C serotonin receptors and α-2 adrenoceptors and for NFPS and Org 24461 to 5-HT7 serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg po in mice and did not induce catalepsy in a dose of 10 mg/kg ip in rats. The ID50 values of NFPS were 21.4 mg/kg and higher than 30 mg/kg ip for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg ip for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg ip) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg ip). Both NFPS and Org 24461 (1-10 mg/kg ip) reversed PCP-induced changes in EEG power spectra in conscious rats. These data support the view that GlyT1 inhibitors may have potential importance in treatment of negative symptoms of schizophrenia.

Original languageEnglish
Pages (from-to)811-825
Number of pages15
JournalPharmacology Biochemistry and Behavior
Issue number4
Publication statusPublished - Mar 2003



  • Antipsychotic agents
  • Antipsychotic tests
  • Anxiolytic tests
  • Electroencephalogram
  • Glycine transporter-1 inhibitors
  • NFPS
  • Negative symptoms of schizophrenia
  • Org 24461
  • [H]Glycine efflux
  • [H]Glycine uptake

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

Cite this

Harsing, L. G., Gacsalyi, I., Szabo, G., Schmidt, E., Sziray, N., Sebban, C., Tesolin-Decros, B., Matyus, P., Egyed, A., Spedding, M., & Levay, G. (2003). The glycine transporter-1 inhibitors NFPS and Org 24461: A pharmacological study. Pharmacology Biochemistry and Behavior, 74(4), 811-825.