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The electroencephalographic (EEG) and cardiovascular effects of milnaciplan hydrochloride (TN-912) were compared with those of imipramine (IMP) and maprotiline (MPT) in rats, guinea pigs and dogs. In conscious rats with chronic electrode implants, TN-912 (10-100 mg/kg, p.o.) had little effect on either the EEG activity or the EEG arousal response to auditory stimulation (2000 Hz). Both IMP (10-100 mg/kg, p.o.) and MPT (10-100 mg/kg, p.o.) tended to increase the drowsy EEG pattern period in the cortical and hippocampal EEG and inhibited the EEG arousal response to auditory stimulation. In conscious rats with a chronic arterial catheter, TN-912 (100 mg/kg, p.o.) slightly elevated the mean blood pressure (MBP) and decreased the heart rate (HR), while both IMP (10-100 mg/kg, p.o.) and MPT (10-100 mg/kg, p.o.) dose-dependently increased MBP and HR. In anesthetized dogs, i.v. injection of TN-912 (1-10 mg/kg), IMP (0.3-10 mg/kg) and MPT (1-20 mg/kg) produced a dose-dependent fall in MBP. IMP and MPT but not TN-912 dose-dependently increased HR. TN-912 did not show typical effects on femoral blood flow. TN-912 (30 mg/kg) had little effect on lead II electrocardiogram (ECG), while IMP and MPT markedly increased height of the T-wave on ECG. In the in vitro study with the isolated guinea pig atrium, TN-912 caused a slight positive inotropic and negative chronotropic effect, while both IMP and MPT showed marked negative inotropic and chronotropic actions. These results suggest that TN-912 has less EEG effect and cardiac toxicity, indicating that TN-912 may be safe in clinical use.

Electroencephalographic and cardiovascular effects of milnaciplan hydrochloride (TN-912), a novel antidepressant.