title: Molecular combination of the dopamine and serotonin scaffolds yield in novel antipsychotic drug candidates - characterization by in vivo experiments.
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.
authors.affiliation: Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich Schiller Universität Jena, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schulze
authors.forename: O
authors.initials: O
authors.lastname: Siol
authors.forename: D
authors.initials: D
authors.lastname: Robaa
authors.forename: F K U
authors.initials: FK
authors.lastname: Mueller
authors.forename: C
authors.initials: C
authors.lastname: Enzensperger
authors.forename: C
authors.initials: C
authors.lastname: Fleck
authors.forename: J
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D002478:Cells, Cultured; D004298:Dopamine / Q000737:chemistry*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000737:chemistry; D011985:Receptors, Serotonin / Q000737:chemistry; D018967:Risperidone / Q000494:pharmacology; D012701:Serotonin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D013778:Tetrazolium Salts; D013844:Thiazoles; D012701:Serotonin; C022616:thiazolyl blue; D006220:Haloperidol; D018967:Risperidone; D002118:Calcium; D004298:Dopamine