title: Design, synthesis, and structure-activity relationship studies of a series of [4-(4-carboxamidobutyl)]-1-arylpiperazines: insights into structural features contributing to dopamine D3 versus D2 receptor subtype selectivity.
abstract: Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for the treatment of substance abuse and neuropsychiatric disorders. However, development of druglike lead compounds with selectivity for the D3 receptor has been challenging because of the high sequence homology between the D3R and the dopamine D2 receptor (D2R). In this effort, we synthesized a series of acylaminobutylpiperazines incorporating aza-aromatic units and evaluated their binding and functional activities at the D3 and D2 receptors. Docking studies and results from evaluations against a set of chimeric and mutant receptors suggest that interactions at the extracellular end of TM7 contribute to the D3R versus D2R selectivity of these ligands. Molecular insights from this study could potentially enable rational design of potent and selective D3R ligands.
authors.affiliation: Organic Chemistry Department, Southern Research Institute , Birmingham, Alabama 35205, United States.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Saini
authors.forename: Guangyan
authors.initials: G
authors.lastname: Zhou
authors.forename: Judith V
authors.initials: JV
authors.lastname: Hobrath
authors.forename: Indira
authors.initials: I
authors.lastname: Padmalayam
authors.forename: Ling
authors.initials: L
authors.lastname: Zhai
authors.forename: J Robert
authors.initials: JR
authors.lastname: Bostwick
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.forename: Shea
authors.initials: S
authors.lastname: McDowell
authors.forename: Eunie
authors.initials: E
authors.lastname: Cho
authors.forename: Leah
authors.initials: L
authors.lastname: McAleer
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000071557:beta-Arrestins