Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores

A series of potent and selective D3 receptor (D3R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds 11, 14, 15a, and 15c revealed favorable D3R affinity (Ki = 12-25.6 nM) and were highly selective for D3R vs D3R (ranging from 264-905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10-20 minute benchtop C–N cross-coupling methodology, affording a broad range of arylated diazaspiro pre-cursors.