Abstract
Serotonin and dopamine play an important role in the aetiology of schizophrenia. Combination
of the structural scaffolds of both neurotransmitters in a single molecule lead to
aromatic [d,g]-bisannelated azecine derivatives, which have been shown to be nanomolar to subnanomolar
dopamine D1-D5 receptor antagonists with a preference for the D1 family. In this work the potential antipsychotic activity of some azecine derivatives
was predicted by their dopamine receptor affinities obtained in vitro from radioligand
binding experiments and conclusively confirmed in vivo (rats) by applying a conditioned
avoidance model. Furthermore, the compounds were tested in vivo for the development
of catalepsy, which is a predictive parameter for extra-pyramidal side-effects caused
by many antipsychotics. The investigated azecines displayed low cytotoxicity, and
the affinities for human dopamine D1-D5 and serotonin 5-HT2 A receptors were in a nanomolar range. In vivo, their antipsychotic activities in the
rat model were comparable with those of haloperidol and risperidone, but revealed
a 2–5 times better therapeutic range with regard to catalepsy. Preliminary tests for
oral bioavailability also revealed promising results for this new class of potential
antipsychotic compounds. In conclusion, our in vivo experiments show that aromatic
[d,g]-annelated azecines represent a novel and advantageous class of potential atypical
neuroleptics.
Key words
5-HT
2 A receptor - dopamine receptor - azecine - antipsychotic - neuroleptic potency - catalepsy
