Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands

A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D₂, D₃, and D₄ receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D₃ dopamine receptor compared to the D₂ receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had K_i values ranging from 0.7 to 3.9 nM for the D₃ receptor with 30- to 170-fold selectivity for the D₃ versus D₂ receptor. Calculated log P values (log P = 2.6–3.6) are within the desired range for passive transport across the blood–brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D₂ and D₃ dopamine receptors generally decreased, (b) the D₃ receptor binding selectivity (D₂:D₃ K_i value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.