title: The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study.
abstract: 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 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-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 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-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 p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. 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 i.p.) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg i.p.). Both NFPS and Org 24461 (1-10 mg/kg i.p.) 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.
authors.affiliation: Division of Preclinical Research, EGIS Pharmaceuticals Ltd., P.O. Box 100, H-1475 Budapest, Hungary. larsing@axelero.hu
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Harsing
authors.forename: Istvan
authors.initials: I
authors.lastname: Gacsalyi
authors.forename: Geza
authors.initials: G
authors.lastname: Szabo
authors.forename: Eva
authors.initials: E
authors.lastname: Schmidt
authors.forename: Nora
authors.initials: N
authors.lastname: Sziray
authors.forename: Claude
authors.initials: C
authors.lastname: Sebban
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tesolin-Decros
authors.forename: Peter
authors.initials: P
authors.lastname: Matyus
authors.forename: Andras
authors.initials: A
authors.lastname: Egyed
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Levay
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D005998:Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D050487:Glycine Plasma Membrane Transport Proteins; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; C479537:Org 24461; C493267:Slc6a9 protein, mouse; C493266:Slc6a9 protein, rat; D005998:Glycine; D012521:Sarcosine