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 D(3)-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 D(2)-like selectivity over D(1) in native porcine striatal tissue. Furthermore, n-propyl analog 5f was found to be a high affinity (K(i)=1.1 nM) D(3) dopamine full agonist with 145-fold selectivity over the D(2) receptor and about 840-fold selectivity over the D(1) receptor.