Author/Authors :
Hervé Geneste، نويسنده , , Wilhelm Amberg، نويسنده , , Gisela Backfisch، نويسنده , , Armin Beyerbach، نويسنده , , Wilfried M. Braje، نويسنده , , Jürgen Delzer، نويسنده , , Andreas Haupt، نويسنده , , Charles W. Hutchins، نويسنده , , Linda L. King، نويسنده , , Daryl R. Sauer، نويسنده , , Liliane Unger، نويسنده , , Wolfgang Wernet، نويسنده ,
Abstract :
In our efforts to further pursue one of the most selective dopamine D3-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D3 antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited Ki values toward the D3 receptor in the nano- to subnanomolar range and high selectivity versus the related D2 dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F = 37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D3 versus D2 selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F < 10%). These data significantly enhance our understanding of the D3 pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.
