Evaluation of N-phenyl homopiperazine analogs as potential dopamine D 3 receptor selective ligands

Article abstract of DOI:10.1016/j.bmc.2013.03.074

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 D ₃ 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.