Neue Liganden an humanen Dopamin- und Serotoninrezeptoren : Assay Entwicklung und Struktur-Wirkungs-Beziehungen
The affinities of several substances, belonging to different structural classes (bisannelated azecines and homoazecines, arylpiperazines bearing a heterocyclic side chain in addition to apomorphine derivatives) were examined at the human 5 HT2A receptors as well as the different dopamine receptor subtypes, in order to identify the structures, whose affinity profile or high subtype selectivity, render them suitable as potential antipsychotics or pharmacological tools for studying dopaminergic and serotonergic neurotransmissions. Their functionality was also partly investigated in a fluorescent calcium assay. For this purpose, the assay facilities, already present in our research group, were extended to encompass radioligand binding assay at HEK D2, HEK D3 and HEK 5 HT2A cell lines beside a fluorescence-based Calcium assay at HEK D3 und HEK 5 HT2A. Furthermore, a new benzindolo derivative, enclosing an oxygen-containing central 11 membered ring was synthesized out of a 7-membered lactone and tryptamine. The obtained hydroxybenzamide derivative was cyclized under Bischler-Napieralski conditions and subsequently reduced to afford a pentacyclic intermediary product. The target compound was obtained after quaternization followed by reduction using Birch conditions. Many of the tested azecines and homoazecines were found to possess an interesting 5-HT2A/D2 binding profile, which render them potential antipsychotics. Concerning the phenylpiperazine derivatives, compounds with pronounced D4-selectivity were identified. Modifications of the A-ring of apomorphine led for the most part to attenuated affinities and loss of selectivity.