Cyanoindole derivatives as highly selective dopamine D-4 receptor partial agonists: Solid-phase synthesis, binding assays, and functional experiments

Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles a nd subsequent incorporation of phenylpiperazine derivatives led to the 2- a nd 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor bin ding studies on the final products 3a-m clearly indicated strong and select ive recognition of the D-4 subtype which is known as a promising target for the treatment of neuropsychiatric disorders. The most interesting binding properties were observed for the 2-aminomethyl-5-cyanoindoles FAUC 299 (3f) and FAUC 316 (3j) (K-i = 0.52 and 1.0 nM, respectively) when the fluoro de rivative 3j proved extraordinary selectivity over D-1, D-2long, D-2short, a nd D-9 (>8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3fj (35 % and 30%, when compared to the full agonist quinpirole).