Cyanoindole Derivatives as Highly Selective Dopamine D₄Receptor Partial Agonists:  Solid-Phase Synthesis, Binding Assays, and Functional Experiments

Abstract

Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles and subsequent incorporation of phenylpiperazine derivatives led to the 2- and 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor binding studies on the final products 3a-m clearly indicated strong and selective 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 derivative 3j proved extraordinary selectivity over D(1), D(2long), D(2short), and D(3) (>8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3f,j (35% and 30%, when compared to the full agonist quinpirole).

Synthesis and in vitro evaluation of iodine labelled pyrazolo[1,5‐a]pyridines as highly selective dopamine D4 receptor ligands

“…For an optimized incorporation of [ 131 I]iodide, the precursor concentration should not be less than 7.5 mM (Figure 2 [16][17][18][19] in order to determine receptor affinity and subtype selectivity. Here, we compare K i values determined for the cold compound % 2 to the binding characteristics of FAUC 113 and to those of compound % 1 which were already published.…”

Chirospecific and Subtype Selective Dopamine Receptor Binding of Heterocyclic Methoxynaphthamide Analogs

“…The mitogenesis experiments were done with a CHO10001A cell line stably transfected with the rat dopamine D 4.2 receptor according to literature [18]. In brief, cells were grown in MEM α-medium supplemented with fetal calf serum, L-glutamine, penicillin G, streptomycin and hygromycin B at 37°C under a humidified atmosphere of 5 % CO 2 Ϫ95 % air at a density of 10,000 cells/well.…”

Synthetic approaches towards indoles on solid phase recent advances and future directions

“…Gmeiner et al 28 modified the indole 2-position by treating the polymer-bound 2-chloromethylindoles 57 with arylpiperazines (Scheme 14). The compounds obtained were found as highly selective dopamine D 4 receptor partial agonists.…”