PMID- 24389121 OWN - NLM STAT- MEDLINE DCOM- 20141125 LR - 20181202 IS - 1873-7862 (Electronic) IS - 0924-977X (Linking) VI - 24 IP - 3 DP - 2014 Mar TI - A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia. PG - 425-36 LID - S0924-977X(13)00340-4 [pii] LID - 10.1016/j.euroneuro.2013.11.009 [doi] AB - 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. CI - Copyright (c) 2013 Elsevier B.V. and ECNP. All rights reserved. FAU - Gil-Ad, Irit AU - Gil-Ad I AD - 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. FAU - Portnoy, Moshe AU - Portnoy M AD - School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel Aviv, Israel. FAU - Tarasenko, Igor AU - Tarasenko I AD - 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. FAU - Bidder, Miri AU - Bidder M AD - 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. FAU - Kramer, Maria AU - Kramer M AD - School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel Aviv, Israel. FAU - Taler, Michal AU - Taler M AD - 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. FAU - Weizman, Abraham AU - Weizman A AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131216 PL - Netherlands TA - Eur Neuropsychopharmacol JT - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology JID - 9111390 RN - 0 (Antipsychotic Agents) RN - 0 (Central Nervous System Stimulants) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (PGW5 compound) RN - 12794-10-4 (Benzodiazepines) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - CK833KGX7E (Amphetamine) RN - J1DOI7UV76 (Phencyclidine) RN - N7U69T4SZR (Olanzapine) RN - OF5P57N2ZX (Alanine) SB - IM MH - Alanine/administration & dosage/adverse effects/*analogs & derivatives/pharmacology MH - Amphetamine/pharmacology MH - Animals MH - Antipsychotic Agents/administration & dosage/adverse effects/*pharmacology MH - Anxiety/drug therapy MH - Benzodiazepines/administration & dosage/adverse effects/*pharmacology MH - Brain/drug effects/metabolism MH - Central Nervous System Stimulants/pharmacology MH - Depression/drug therapy MH - Dizocilpine Maleate/pharmacology MH - Dose-Response Relationship, Drug MH - Drug Evaluation, Preclinical MH - Excitatory Amino Acid Antagonists/pharmacology MH - Exploratory Behavior/drug effects MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Motor Activity/drug effects MH - Olanzapine MH - Phencyclidine/pharmacology MH - Psychomotor Agitation/drug therapy/etiology MH - Schizophrenia/*drug therapy MH - Social Behavior OTO - NOTNLM OT - Antipsychotic OT - Glutamate OT - N-methyl-d-aspartate receptor (NMDA-R) OT - Negative symptoms OT - Positive symptoms OT - Schizophrenia EDAT- 2014/01/07 06:00 MHDA- 2014/12/15 06:00 CRDT- 2014/01/07 06:00 PHST- 2013/08/21 00:00 [received] PHST- 2013/11/18 00:00 [revised] PHST- 2013/11/19 00:00 [accepted] PHST- 2014/01/07 06:00 [entrez] PHST- 2014/01/07 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] AID - S0924-977X(13)00340-4 [pii] AID - 10.1016/j.euroneuro.2013.11.009 [doi] PST - ppublish SO - Eur Neuropsychopharmacol. 2014 Mar;24(3):425-36. doi: 10.1016/j.euroneuro.2013.11.009. Epub 2013 Dec 16.