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

Aixiao Li, Yogesh Mishra, Maninder Malik, Qi Wang, Shihong Li, Michelle Taylor, David E. Reichert, Robert R. Luedtke, Robert H. MacH

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13 Scopus citations


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 Ki 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 Ki value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.

Original languageEnglish
Pages (from-to)2988-2998
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number11
StatePublished - Jun 1 2013


  • D dopamine receptors
  • D-like receptors
  • Dopamine
  • Homopiperazine analogs
  • Receptor subtype selective ligands


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