Pharmacological evaluation of a novel assay for detecting glycine transporter 1 inhibitors and their antipsychotic potential.
Multiple lines of evidence support the notion that hypofunction of glutamatergic neurotransmission is involved in the pathophysiology of schizophrenia. Moreover, glycine and glycine modulators have beneficial effects in patients with schizophrenia, particularly when added on to existing therapy. As glycine is an obligatory co-agonist at the NR1 subunit of the NMDA receptor, blockade of glycine uptake at the glycine transporter type-1 (GlyT1) can enhance low glutamatergic tone. L-687,414 is an antagonist at the glycine modulatory site of the NMDA complex and, behaviorally, increases locomotion. A series of GlyT1 inhibitors along with other psychoactive compounds were examined for their ability to enhance or inhibit the action of L-687,414. GlyT1 inhibitors and the other compounds were examined initially for effects on [(3)H]-glycine uptake in CHO cells expressing hGlyT1b cDNA and for their ability to displace the NMDA-glycine site ligand [(3)H]-L-689,560 from isolated rat forebrain membrane preparations. The in vivo activity of these compounds was determined in mice by measuring their ability to prevent L-687,414-induced hyperlocomotion. GlyT1 inhibitors blocked [(3)H]-glycine uptake in cells expressing the human transporter; other compounds had little or no activity. None of the compounds had affinity for the glycine site of the NMDA receptor complex. Hyperlocomotion induced by L-687,414 was dose-dependently reduced by GlyT1 inhibitors and antipsychotic drugs but not by morphine, fluoxetine or a moderate dose of diazepam. Therefore, this behavioral approach can reliably detect GlyT1 inhibitors which, in turn, may have some activity in common with drugs having antipsychotic effects.
Alberati
Daniela
D
CNS Research, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
Moreau
Jean-Luc
JL
Mory
Roland
R
Pinard
Emmanuel
E
Wettstein
Joseph G
JG
D000634:Aminoquinolines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D018684:Glycine Agents / Q000494:pharmacology*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D000634:Aminoquinolines; D014150:Antipsychotic Agents; D018076:DNA, Complementary; D018691:Excitatory Amino Acid Antagonists; D005473:Fluoxetine; D005998:Glycine; D018684:Glycine Agents; D050487:Glycine Plasma Membrane Transport Proteins; D009020:Morphine; D014179:Neurotransmitter Uptake Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; C074617:4-trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline