title: Sarcosine-Based Glycine Transporter Type-1 (GlyT-1) Inhibitors Containing Pyridazine Moiety: A Further Search for Drugs with Potential to Influence Schizophrenia Negative Symptoms.
abstract: We have synthesized a novel series of N-substituted sarcosines, analogues of NFPS (N-[3-(biphenyl-4- yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine), as type-1 glycine transporter (GlyT-1) inhibitors. Several compounds incorporated a diazine ring inhibited recombinant hGlyT-1b expressed permanently in CHO cells and GlyT-1 in rat brain synaptosomal preparations. A structure-activity relationship for the newly synthesized compounds was obtained and discussed on the ground of their GlyT-1 inhibitory potencies. Replacement of the biphenyl-4-yloxy moiety in NFPS with a 5-pyridazinylphenoxy moiety (compounds 3, 4, 5, and 6) or a 2-phenyl-5- pyridazinyloxy moiety (compounds 10, 11, and 12) afforded compounds exhibiting potent inhibition on GlyT-1 activity. The GlyT-1 inhibitory properties of NFPS analogues, in which sarcosine was closed into a ring forming (methylamino)pyridazine-3-(2H)-one, were markedly reduced (compounds 13 and 14). The pyridazine-containing GlyT-1 inhibitors with in vitro GlyT-1 inhibitory potency also enhanced extracellular glycine concentrations in conscious rat striatum as was measured by microdialysis technique. In contrast to NFPS, sarcosine-based pyridazine containing GlyT-1 inhibitors failed to evoke compulsive running behavior whereas they inhibited phencyclidine- induced hypermotility in mice. It is believed that increase of extracellular concentrations of glycine by inhibition of its reuptake may probably influence positively glutamate N-methyl-D-aspartate (NMDA)-type ionotropic receptors in the central nervous system. This may have importance in the treatment of neuropsychiatric disorders associated with hypofunctional NMDA receptor-mediated glutamatergic neurochemical transmission. Thus, impaired NMDA receptor functions have been shown to be involved in the development of the negative symptoms and the cognitive deficit of schizophrenia and the treatment of these symptoms is the possible clinical indication of GlyT-1 inhibitors including those containing pyridazine moiety.
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Harsing
authors.forename: Julia
authors.initials: J
authors.lastname: Timar
authors.forename: Geza
authors.initials: G
authors.lastname: Szabo
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Udvari
authors.forename: Katalin M
authors.initials: KM
authors.lastname: Nagy
authors.forename: Bernadett
authors.initials: B
authors.lastname: Marko
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zsilla
authors.forename: Andrea
authors.initials: A
authors.lastname: Czompa
authors.forename: Pal
authors.initials: P
authors.lastname: Tapolcsanyi
authors.forename: Akos
authors.initials: A
authors.lastname: Kocsis
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Nagyvarad ter 4, Hungary. lharsing@t-email.hu.
authors.forename: Peter
authors.initials: P
authors.lastname: Matyus
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012521:Sarcosine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; D011724:Pyridazines; C493268:SLC6A9 protein, human; C062482:pyridazine; D012521:Sarcosine