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 2446 1), was studied. NFPS and Org 24461 inhibited the uptake of [H-3]glycine in hippocampal synaptosomal preparation with IC50 values of 0.022 and 2.5 muM. Neither NFPS nor Org 24461 (0.1 muM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D-1 and D-2 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 muM concentrations, binding affinity was measured for NFPS to 5-HT2A and 5-HT2C serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT7 serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [H-3]glycine efflux from superfused rat hippocampal slices preloaded with [H-3]glycine. NFPS and Org 24461 (0.1 mM) did not influence [H-3]glycine efflux, however, they inhibited glycine-induced [H-3]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 GlyT I inhibitors may have potential importance in treatment of negative symptoms of schizophrenia. (C) 2002 Elsevier Science Inc. All rights reserved.