title: Dopamine D4 ligands and models of receptor activation: 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole and related heteroarylmethylarylpiperazines exhibit a substituent effect responsible for additional efficacy tuning.
abstract: A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.
authors.affiliation: Department R4ND, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6115, USA. andrew.o.stewart@abbott.com
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Steve P
authors.initials: SP
authors.lastname: Latshaw
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.forename: Pramila A
authors.initials: PA
authors.lastname: Bhatia
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Nelson
authors.forename: Marc A
authors.initials: MA
authors.lastname: Terranova
authors.forename: Marian T
authors.initials: MT
authors.lastname: Namovic
authors.forename: Diana L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: Loan N
authors.initials: LN
authors.lastname: Miller
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050638:Receptors, Dopamine D4; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001562:Benzimidazoles; C493599:DRD4 protein, human; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4