Therapeutic Area(s): Schizophrenia
Phase of Development: Phase II
TGOF02N is a 5HT2/D2 atypical antipsychotic. Like other atypical
antipsychotics TGOF02N has the highest receptor binding for the
dopamine D2 and D3 receptors, the serotonin 5HT2C and 5HT2A receptors,
the adrenergic 1 receptor and the histamine H1 receptor, and is
moderate affinity for the D1, D4 and 5HT1A receptors as well.
TGOF02N HCl exhibited dose-related antipsychotic activity in
several animal behavioral models. TGOF02N HCl inhibited amphetamine-induced
hyperactivity in mice over a dose range of 0.0625 to 0.5 mg/kg
(ID50 value = 0.16 mg/kg). Its activity was similar to that
of risperidone and haloperidol, and greater than that of clozapine.
The ability of TGOF02N HCl (0.0625 to 0.5 mg/kg) to inhibit
apomorphine-induced climbing behavior in mice and apomorphine-induced
hyperactivity in mice suggested its potential beneficial effects
on the positive symptoms of schizophrenia. Because of its alpha-adrenergic
antagonist activity, TGOF02N HCl protected mice against noradrenaline-induced
lethality (ED50=0.05 mg/kg); this suggested a potential to mitigate
the positive symptoms and ameliorate the cognitive symptoms
of schizophrenia; its potency in this test was similar to that
of risperidone. TGOF02N HCl also inhibited MK-801-induced hyperactivity
in mice (ID50=0.23 mg/kg), which suggested its potential beneficial
effect on the negative symptoms of schizophrenia. TGOF02N HCl
inhibited the 5HT2A receptor in the DOI-induced head twitch
test in mice. This suggested that TGOF02N HCl might provide
an amelioration of both positive and negative symptoms of schizophrenia
with a low incidence of extrapyramidal symptoms. TGOF02N HCl
also demonstrated 5HT2C receptor antagonism in the mCPP-induced
hypolocomotion test in rats.
TGOF02N HCl did not protect mice against physostigmine-induced
lethality at oral dosages of 4 or 8 mg/kg. This 8 mg dose was
approximately 33 times the ID50 value for TGOF02N HCl with respect
to the inhibition of apomorphine-induced climbing behavior (0.24
mg/kg), which is associated with antipsychotic activity. This
suggested that TGOF02N HCl would have a low incidence of antimuscarinic
side effects at effective antipsychotic doses. The ID50 value
for TGOF02N HCl (18.40 mg/kg) with respect to apomorphine induced
climbing assay in mice, suggests a potential lack of extrapyramidal
side effects at antipsychotic doses. TGOF02N HCl showed an antagonistic
effect on dopamine D1 receptors (ID50 = 0.31 mg/kg) in the SKF38393-induced
grooming test in mice, which suggested a possibility of lesser
extrapyramidal side effects.
Three Phase I trials have been conducted in normal healthy males.
Two were single dose, dose escalation studies and the third was
a multiple dose, dose escalation study.
The single dose studies showed that in the oral dose range 0.5
to 1.5 mg pharmacokinetics were linear with Tmax between 2 and
4 hours and 1/2 between 2 and 3 hours.
In the multiple dose study 0.5, 1.0, or 1.5mg was given daily
for 7 days. TGOF02N was rapidly absorbed with Tmax of about 2.5
hours and 1/2 from 3.24 to 3.84 on both days 1 and 7. There was
In both studies, the most frequent adverse event was postural
hypotension manifested by increased heart rate, decreased standing
blood pressure, and in some cases dizziness.
Electrocardiographic examinations revealed no abnormalities including
no changes in QTc.
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