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

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.

Figure 1. Total weight gain and food intake in female rats treated with Olz and Olz derivatives.

A. Total body weight gain (g), B. Total food intake (g) in female Sprague Dawley rats treated with Olz, OlzEt, OlzHomo (3 mg/kg or 6 mg/kg), or vehicle (Control) for 5 weeks. The data points are the mean ± SEM, **P<0.01 and ***P<0.001 vs. Control.

Figure 2. Cumulative weight gain and food intake in female rats treated with Olz and Olz derivatives.

A. Cumulative body weight gain (g), B. Cumulative food intake (g) in female Sprague Dawley rats treated with Olz, OlzEt, OlzHomo (3 mg/kg or 6 mg/kg), or vehicle (Control) for 5 weeks. The data points are the mean ± SEM. A. *P<0.05, **P<0.01: Olz 3 mg/kg vs. control. ^## P<0.01, ^### P<0.001: Olz 6 mg/kg vs. Control. B. **P<0.01, ***P<0.001: Olz 6 mg/kg vs. Control. (*: Control, Δ: Olz 3 mg/kg, ▴: 6 mg/kg, ◊: OlzEt 3 mg/kg, ♦: OlzEt 6 mg/kg, o: OlzHomo 3 mg/kg and •: OlzHomo 6 mg/kg).

Figure 3. Hormonal profiles in female rats treated with Olz and Olz derivatives.

A. Plasma Leptin (PM), B. Plasma Adiponectin (pg/ml), C. Plasma insulin (PM), D. Plasma Glucose (mmol/L) in female Sprague Dawley rats treated with Olz, OlzEt, OlzHomo (3 mg/kg or 6 mg/kg), or vehicle (Control) for 5 weeks. The data points are the mean ± SEM, *P<0.05 and **P<0.01 vs. Control.