title: Dopamine/serotonin receptor ligands. 10: SAR Studies on azecine-type dopamine receptor ligands by functional screening at human cloned D1, D2L, and D5 receptors with a microplate reader based calcium assay lead to a novel potent D1/D5 selective antagonist.
abstract: On the basis of the benz[d]indolo[2,3-g]azecine derivative 1 (LE300), structure-activity relations were investigated in order to identify the pharmacophore in this new class of ligands. Various structural modifications were performed and the inhibitory activities at human cloned D(1), D(2L), and D(5) receptors were measured by using a simple fluorescence microplate reader based calcium assay. Subsequently, the affinities of active compounds were estimated by radioligand binding experiments. Deleting one of the aromatic rings as well as replacing it by a phenyl moiety abolishes the inhibitory activities almost completely. Contraction of the 10-membered central ring decreases them significantly. The replacement of indole by thiophene or N-methylpyrrole reduces the inhibitory activity, whereas replacing the indole by benzene increases it. Finally, the hydroxylated dibenz[d,g]azecine derivative 11d (LE404) was found to be more active than the lead 1 in the functional calcium assay as well as in radioligand displacement experiments.
authors.affiliation: Institute of Pharmacy, University of Bonn, D-53121 Bonn, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hoefgen
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.forename: Patrick
authors.initials: P
authors.lastname: Mohr
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Schramm
authors.forename: Sherif A F
authors.initials: SA
authors.lastname: Rostom
authors.forename: Hussein
authors.initials: H
authors.lastname: El-Subbagh
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schweikert
authors.forename: Dirk R
authors.initials: DR
authors.lastname: Rudolf
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D065127:Dopamine D2 Receptor Antagonists; D005470:Fluorometry; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C508806:7-methyl-2,3-dimethoxy-5,6,7,8,9,14-hexahydrodibenz(d,g)azecine; D001555:Benzene Derivatives; D065127:Dopamine D2 Receptor Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D008024:Ligands; D011758:Pyrroles; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013876:Thiophenes; C113776:dopamine D2L receptor; D050641:Receptors, Dopamine D5; D002118:Calcium