In vivo pharmacological evaluations of novel olanzapine analogues in rats: A potential new avenue for the treatment of schizophrenia

Journal article


Jafari, Somayeh, Huang, Xu-Feng, Andrews, Jessica L. and Fernandez-Enright, Francesca. (2013). In vivo pharmacological evaluations of novel olanzapine analogues in rats: A potential new avenue for the treatment of schizophrenia. PLoS ONE. 8(12), pp. 1 - 10. https://doi.org/10.1371/journal.pone.0080979
AuthorsJafari, Somayeh, Huang, Xu-Feng, Andrews, Jessica L. and Fernandez-Enright, Francesca
Abstract

Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis.

Year2013
JournalPLoS ONE
Journal citation8 (12), pp. 1 - 10
PublisherPublic Library of Science
ISSN1932-6203
Digital Object Identifier (DOI)https://doi.org/10.1371/journal.pone.0080979
Scopus EID2-s2.0-84892598888
Open accessOpen access
Page range1 - 10
Research GroupSchool of Behavioural and Health Sciences
Publisher's version
License
Place of publicationUnited States of America
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