title: Attenuated Weight Gain with the Novel Analog of Olanzapine Linked to Sarcosinyl Moiety (PGW5) Compared to Olanzapine.
abstract: Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. michalt@post.tau.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Taler
authors.affiliation: Department of Psychology, Bar Ilan University, 52900, Ramat Gan, Israel.|Gonda (Goldschmied) Brain Research Center, Bar Ilan University, 52900, Ramat Gan, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vered
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rea
authors.initials: R
authors.lastname: Globus
authors.affiliation: Department of Psychology, Bar Ilan University, 52900, Ramat Gan, Israel.|Gonda (Goldschmied) Brain Research Center, Bar Ilan University, 52900, Ramat Gan, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Shbiro
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Research Unit, Geha Mental Health Center, Petah Tikva, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
authors.affiliation: Department of Psychology, Bar Ilan University, 52900, Ramat Gan, Israel.|Gonda (Goldschmied) Brain Research Center, Bar Ilan University, 52900, Ramat Gan, Israel.
authors.forename: Aron
authors.initials: A
authors.lastname: Weller
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gil-Ad
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D000077152:Olanzapine; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D012521:Sarcosine / Q000737:chemistry; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; C000593032:PGW5 compound; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; D001569:Benzodiazepines; D000077152:Olanzapine; D000409:Alanine; D012521:Sarcosine
keywords: Neuropeptide Y (NPY); Olanzapine; PGW5; Pro-opiomelanocortin (POMC); Weight gain