title: A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia.
abstract: Schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl-D-aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25-50mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5mg/kg ip) hyperactivity. PGW5 (25mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis.
  
  
  CONCLUSIONS
  PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression.
authors.affiliation: Felsenstein Medical Research Center, Campus Rabin, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gil-Ad
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Portnoy
authors.affiliation: Felsenstein Medical Research Center, Campus Rabin, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Igor
authors.initials: I
authors.lastname: Tarasenko
authors.affiliation: Felsenstein Medical Research Center, Campus Rabin, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Bidder
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Felsenstein Medical Research Center, Campus Rabin, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Taler
authors.affiliation: Felsenstein Medical Research Center, Campus Rabin, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva 49100, Israel; Research Unit, Geha Mental Health Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: aweizman@clalit.org.il.
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology; D011595:Psychomotor Agitation / Q000188:drug therapy / Q000209:etiology; D012559:Schizophrenia / Q000188:drug therapy*; D012919:Social Behavior
chemical_list: D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; C000593032:PGW5 compound; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D000661:Amphetamine; D010622:Phencyclidine; D000077152:Olanzapine; D000409:Alanine
keywords: Antipsychotic; Glutamate; N-methyl-d-aspartate receptor (NMDA-R); Negative symptoms; Positive symptoms; Schizophrenia