Neue Dibenz[d,g]azecine als hochaffine Liganden an humanen Dopaminrezeptoren

Mohr, Patrick

The purpose of this thesis was, based on the highly potent dopamine receptor ligand LE 404 (3-hydroxy-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecine), to synthesize novel substituted dibenz[d,g]azecine derivatives and parts of this structure, in order to determine the binding properties of these compounds by radioligand binding studies and a functional Ca2+-assay. This should lead to structure activity relationships (SAR) of this new class of dopamine receptor antagonists, to novel tools in dopamine receptor research and to novel potential antipsychotic drugs with fewer side effects by realizing new receptor binding profiles at the different dopamine receptor subtypes. Dibenz[d,g]azecines without substituents at the aromatic rings were prepared out of 1-phenyl-3,4-dihydroisoquinoline by quaternisation with bromoethanol and reduction - or reduction and treatment with 2-ethyloxirane, respectively -, cyclisation with polyphosphoric acid, quaternisation of the resulting dibenzo[a,h]quinolizines with alkylhalides or m-CPBA, and finally reductive ring cleavage by using Birch conditions. Substituted derivatives were prepared via hydroxyethyl-benzamides by protection of the alcohol (if necessary), followed by a multistep procedure applying a Bischler-Napieralski-cyclisation using POCl3, yielding the corresponding dibenzo[a,h]quinolizines, quaternisation by alkylhalides and subsequent ring cleavage of the central C-N-bond under Birch conditions or by hydrogenolysis of the quaternary quinolizinium salts by H2/PtO2. Also treatment with ethyl-chloroformate and conversion into a urethane by NaBH3CN, followed by reduction leads to further azecines. Cleavage of quaternary quinolizinium salts performed with NaH/DMSO leads to novel azecines with a ketone moiety in position 14. Compound C could be obtained by reduction of the corresponding lactame derivatives. Evaluation of MS-data of all the novel dibenz[d,g]azecines synthesized and their relevant precursors yielded in a "dibenz[d,g]azecine-database" which showed to be very helpful in monitoring the synthesis and identification of actual and future target compounds. Competitive radioligand binding studies and functional assays were performed at human cloned dopamine receptors (hD1, hD2L, hD3 and hD5), stably expressed in HEK or CHO cell lines, respectively and resulted in the identification of numerous new potent antidopaminergic ligands with a strong correlation of affinities and substitution patterns. The most promising compound is the 4-chlorinated LE 404 with subnanomolar affinities at the hD1- and picomolar affinities at the hD5-receptor subtype.

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Mohr, Patrick: Neue Dibenz[d,g]azecine als hochaffine Liganden an humanen Dopaminrezeptoren. 2005.

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