Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D3 receptor-selective full agonist ligand

This work describes the identification of a novel class of octahydrobenzo[f]quinolines as dopamine D₃-selective full agonists. We developed a facile method that utilizes Suzuki coupling for easy incorporations of various substituted pendant rings into the scaffold. A small focused library of octahydrobenzo[f]quinolines 5 was synthesized, and these compounds demonstrated at least 14-fold D₂-like selectivity over D₁ in native porcine striatal tissue. Furthermore, n-propyl analog 5f was found to be a high affinity (K_i = 1.1 nM) D₃ dopamine full agonist with 145-fold selectivity over the D₂ receptor and about 840-fold selectivity over the D₁ receptor.