Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D₃ dopamine receptor selective ligands

A series of substituted 1H-indolyl carboxylic acid amides that contain a N-(2-methoxyphenyl)piperazine or N-(2-fluoroethoxy)piperazine group were synthesized and their affinities for human dopamine D₂, D ₃, and D₄ receptors were determined. Two of these compounds, 14a and 14b, displayed high binding affinity at D₃ (K _i = 0.18 and 0.4 nM, respectively), and selectivity for D ₃vs. D₂ receptors (87-fold and 60-fold, respectively). These two compounds had low binding affinity at D₄ receptors and σ receptor sites. The intrinsic activity of these compounds at D ₂ and D₃ receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay; both 14a and 14b were found to be partial agonists. Furthermore, for compound 14a, the log D value of 2.85 suggested it has suitable lipophilicity for crossing the blood-brain-barrier.