title: Structure-activity relationships for a novel series of dopamine D2-like receptor ligands based on N-substituted 3-aryl-8-azabicyclo[3.2.1]octan-3-ol.
abstract: Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K(i)(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2(L)R- or hD3R-transfected HEK 293 cells (31, K(i)(D2R/D3R) = 33.4:15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K(i)(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.
authors.affiliation: Medicinal Chemistry Section, National Institute on Drug Abuses, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Noel M
authors.initials: NM
authors.lastname: Paul
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; D008024:Ligands; D017448:Receptors, Dopamine D2
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