4-HETEROCYCLYLPIPERIDINES AS SELECTIVE HIGH-AFFINITY LIGANDS AT THE HUMAN DOPAMINE D4 RECEPTOR

enyl)-3-(1-(4-chlorobenzyl)piperidin-4-yl)pyrazole (3) was identified from screening of the Merck sample collection as a human dopamine D4 ( hD4) receptor ligand with moderate affinity (61 nM) and 4-fold selecti vity over human D2 (hD2) receptors. Four separate parts of the molecul e have been examined systematically to explore structure-activity rela tionships with respect to hD4 affinity and selectivity over other dopa mine receptors. It was found that the 4-chlorophenyl group attached to the pyrazole is optimal, as is the 4-substituted piperidine. The lipo philic group on the basic nitrogen is more amenable to change, with th e optimal group found to be a phenethyl. The aromatic heterocyle can b e altered to a number of different groups, with isoxazoles and pyrimid ines showing improved affinities. This heterocycle can also be advanta geously alkylated, improving the selectivity of the compounds over D2 receptors. It is hypothesized that the conformation around the bond jo ining the aromatic heterocycle to the piperidine is important for D4 a ffinity, based on crystal structures of isoxazoles (29 and 30) and on a conformationally constrained compound (28). Putting all the favorabl e changes together led to the discovery that ethyl-3-(1-(2-phenlethyl) piperidine-4-yl)isoxazole (36) is a nanomolar antagonist at human dopa mine D4 receptors with >500-fold selectivity over hD2 and >200-fold se lectivity over hD3. Compound 36 is an antagonist of hD4 receptors with good oral bioavailability of 38%, a half life of 2 h, and brain level s 10-fold higher than plasma levels.