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

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 o...

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Published in:Pharmacology, biochemistry and behavior biochemistry and behavior, 2003-03, Vol.74 (4), p.811-825
Main Authors: Harsing, Laszlo G, Gacsalyi, Istvan, Szabo, Geza, Schmidt, Eva, Sziray, Nora, Sebban, Claude, Tesolin-Decros, Brigitte, Matyus, Peter, Egyed, Andras, Spedding, Michael, Levay, Gyorgy
Format: Article
Language:English
Subjects:
[ 3H]Glycine efflux
[ 3H]Glycine uptake
Amino Acid Transport Systems, Neutral - antagonists & inhibitors
Amino Acid Transport Systems, Neutral - metabolism
Animals
Antipsychotic agents
Antipsychotic tests
Anxiolytic tests
Biological and medical sciences
Electroencephalogram
Glycine - antagonists & inhibitors
Glycine - metabolism
Glycine Plasma Membrane Transport Proteins
Glycine transporter-1 inhibitors
Hippocampus - drug effects
Hippocampus - metabolism
Male
Medical sciences
Mice
Negative symptoms of schizophrenia
Neuropharmacology
NFPS
Org 24461
Pharmacology. Drug treatments
Protein Binding - drug effects
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Rats
Rats, Wistar
Sarcosine - analogs & derivatives
Sarcosine - chemistry
Sarcosine - pharmacology
Stereotyped Behavior - drug effects
Stereotyped Behavior - physiology
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Summary: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 IC 50 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, D 1 and D 2 dopamine receptors, and 5-HT 1A and 5-HT 2A serotonin receptors in membranes prepared from rat brain or to cloned 5-HT 6 and 5-HT 7 receptors. At 10 μM concentrations, binding affinity was measured for NFPS to 5-HT 2A and 5-HT 2C serotonin receptors and α-2 adrenoceptors and for NFPS and Org 24461 to 5-HT 7 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 ID 50 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.
ISSN:0091-3057
1873-5177
DOI:10.1016/S0091-3057(02)01078-X