1-(3-cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one: A selective high-affinity antagonist for the human dopamine D-4 receptorwith excellent selectivity over ion channels

After the requirement of pseudocycle formation in the ureas 3 and 7 for hD( 4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2 -oxo-1,3-dihydroimidazol-2-yl)piperidine . Optimization studies were carrie d out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over a ll other receptors while retaining the good pharmacokinetic properties of t he lead. After initial preparation of 8 as a minor component in a low-yield ing reaction, a novel and regioselective "four-step/one-pot'' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents atta ched to the 3-, 4-, or B-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater Selectivity( > 1000-foId) was ultimately achieved by meta substitu tion of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopami ne subtypes, but only 32 has > 1000-fold selectivity over-all the key count erscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological to ol to investigate the role of the D-4 receptor.