Evaluation of the behavioral and pharmacokinetic profile of SYA013, a homopiperazine analog of haloperidol in rats

Abstract

SYA013, a homopiperazine analog of haloperidol, was further evaluated for antipsychotic potential using additional animal models. Previously, SYA013 was tested in mice with an antipsychotic screening model in which it inhibited apomorphine induced climbing behavior, indicating antagonism of the dopaminergic system and the potential for use in the treatment of schizophrenia. In this study, SYA013 was shown to inhibit both d-amphetamine-induced locomotor activity in rats and conditioned avoidance response (CAR) in rats in a dose dependent manner and in the case of CAR, without producing any escape failure responses (EFRs), two tests predictive of antipsychotic action. The selective 5HT(1A) antagonist WAY100,635 was used to determine if binding of SYA013 to the 5HT(1A) receptor contributed to suppression of CAR. The results indicated that 0.63mg/kg WAY100,635 did not have a significant effect on the inhibition of CAR by SYA013. Pharmacokinetic parameters in brain and plasma were determined for SYA013. A log brain/plasma concentration ratio at a t(max) of 1.48 suggests that SYA013 readily crosses the blood brain barrier (BBB). The hypothesis that binding of SYA013 to the 5HT(1A) receptor contributed to the lack of significant catalepsy was investigated using the 5HT(1A) antagonist WAY100,635. The results of acute and semi-chronic tests suggest that binding to the 5HT(1A) receptor alone did not significantly account for the lack of catalepsy. Lack of catalepsy was preserved after the semi-chronic challenge with SYA013. These tests further indicate that SYA013 has a pharmacological profile with the potential for use in the treatment of neuropsychiatric diseases. In addition, the 5HT(1A) receptor does not appear to play a significant role in the pharmacological profile of SYA013.

Fig. 1

Time profile of plasma and brain concentrations of SYA013. Blood plasma and brain tissue levels as SYA013 after 2.09 mg/kg iv (A) and 12.5 mg/kg iv (B).

Fig. 2

Locomotor effects of d-amphetamine after pre-injection by ip (A) or iv (B) with vehicle or SYA013. ***Indicates p<0.001 compared with the vehicle/d-amphetamine group, (one-way ANOVA with post hoc Bonferroni tests). n= 4–8 rats/group.

Fig. 3

Reduction by SYA013 of two-way active avoidance behavior in rats. * indicates p<0.05 compared with the vehicle treated group, (Kruskall-Wallis with Dunn's post test). n= 5 rats/group.

Fig. 4

Conditioned avoidance behavior in rats was significantly influenced by the dose of SYA013 (p<0.05), but not by pretreatment with WAY100,635. Interaction factors were also not significant. (two-way ANOVA). n= 5–6 rats/group.

Fig. 5

Pre-treatment of rats with the 5HT_1A receptor antagonist WAY100,635 did not increase catalepsy when compared to saline pre-treatment. No significant effects of treatment, pretreatment, or interaction were found (two-way ANOVA). n=5 rats per group.

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