title: Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands.
abstract: 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 logP values (logP=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.
authors.affiliation: Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO 63110, USA.
authors.forename: Aixiao
authors.initials: A
authors.lastname: Li
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Mishra
authors.forename: Maninder
authors.initials: M
authors.lastname: Malik
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D005576:Colforsin / Q000737:chemistry; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000737:chemistry; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D050638:Receptors, Dopamine D4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D005576:Colforsin; D000262:Adenylyl Cyclases