The
antipsychotic drug zotepine [ZTP; 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-
amine] is known to have not only atypical
antipsychotic effects but also antidepressive effects in
schizophrenia patients.
Norzotepine [
norZTP;
N-desmethylzotepine, 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N-methylethan-1-
amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized
norZTP through several in vitro studies and in animal models of
psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall
neurotransmitter receptor binding profiles,
norZTP showed 7- to 16-fold more potent
norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and
norZTP showed good brain permeability when administered individually in mice, although
norZTP was not detected in either plasma or brain after
intraperitoneal injection of ZTP. In the
methamphetamine-induced hyperlocomotion test in mice,
norZTP and ZTP showed similar
antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP,
norZTP did not induce
catalepsy up to 10 mg/kg i.p.
norZTP significantly antagonized the
hypothermia induced by
reserpine [(3beta,16beta,17alpha,18beta,20alpha)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-
carboxylic acid methyl
ester], suggesting in vivo inhibition of the
norepinephrine transporter. In the forced-swim test,
norZTP exerted an
antidepressant-like effect at the effective doses for its
antipsychotic action, whereas ZTP neither antagonized
reserpine-
induced hypothermia nor showed
antidepressant-like effect. These results collectively demonstrate that
norZTP exerts more potent inhibitory action than ZTP on
norepinephrine transporters both in vitro and in vivo, presumably accounting for its
antidepressant-like effect and low EPS propensity. Given that
norZTP is the major metabolite observed in humans,
norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.