title: Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands.
abstract: Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.
authors.affiliation: Institut für Pharmazeutische Chemie, Johann Wolfgang Goethe-Universität, Marie Curie Strasse 9, 60439 Frankfurt am Main, Germany.
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Mach
authors.forename: Anneke E
authors.initials: AE
authors.lastname: Hackling
authors.forename: Sylvie
authors.initials: S
authors.lastname: Perachon
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ferry
authors.forename: Camille G
authors.initials: CG
authors.lastname: Wermuth
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Schwartz
authors.forename: Pierre
authors.initials: P
authors.lastname: Sokoloff
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C493593:DRD3 protein, human; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D044005:Tetrahydroisoquinolines; C120565:BP 897