Poster Presenter

Novel potential D1/D5/5-HT2-selective antipsychotics - from design and synthesis via in vitro to in vivo
Jochen Lehmann, Maria Schulze, Franziska Müller, Oliver Siol, Christoph Enzensperger, Christian Fleck
Germany

Serotonin (1) plays, next to dopamine (2), an important role in the pathophysiology of schizophrenia. Hence, combining the basic indol-3-ylethylamine and phenylethylamine structures of both neurotransmitters in one molecule as it is done in compounds 3-5 was supposed to yield in novel atypical neuroleptics. The moderately rigidisized azecines 5, predominantly with alkyl = CH3 (LE300) but not compounds 3 and 4 showed nanomolar to subnanomolar affinities for D and 5-HT2 receptors and were subjected to further structure optimization, always guided by radioligand binding experiments using human D1 - D5 and the human 5-HT2A receptors stably cloned in HEK or CHO cells. Next to the benz-indoloazecines also dibenz-derivatives (6) turned out to be highly potent 5HT2A and dopamine receptor antagonists, preferently at the D1 family. The most promising compounds were tested for their cytotoxicity on human glia cells and then subjected to in vivo investigations (rats) in a pole jump conditioned avoidance model in order to find out whether the pharmacodynamic and pharmacokinetic properties are suitable to possibly use the new compounds as neuroleptics. Furthermore, the compounds were tested in vivo on development of catalepsy, which is a known side effect of many antipsychotics, e.g. haloperidol3. In conclusion, nearly the entire preclinical route from structure design, synthesis, lead identification, lead optimisation, in vitro screening, toxicology and in vivo screening has been performed in academia and a novel type of atypical neuroleptic with advantages compared to haloperidol was found.