title: Dopamine/serotonin receptor ligands, part III [1]: synthesis and biological activities of 7, 7'-alkylene-bis-6, 7, 8, 9, 14, 15-hexahydro-5H-benz[d]indolo[2, 3-g]azecines -- application of the bivalent ligand approach to a novel type of dopamine receptor antagonist.
abstract: A series of 7, 7'-alkylene-bridged dimers(7a-e) of the benz [d]indolo[3, 2-f]azecine derivative LE300 was synthesized. Affinity and functional activity at dopamine D(1) and D(2) receptors were estimated by radioligand binding and a functional Ca(2+) assay. All the new bivalent ligands showed significant binding affinities to both D(1) and D(2) receptors with an optimal distance between the two monomeric recognition units of 6 methylene moieties. The D(1)/D(2)-selectivity pattern was dependent on the spacer length. No (7a, b) or only moderate (7c-e) functional activity was detected for all bivalent compounds by measuring the inhibition of agonist-induced increase in intracellular Ca(2+).
authors.affiliation: Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, University of Jena, Jena, Germany.
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
authors.forename: Stefan
authors.initials: S
authors.lastname: Lankow
authors.forename: Barbara
authors.initials: B
authors.lastname: Hoefgen
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D000465:Algorithms; D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D005456:Fluorescent Dyes; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*
chemical_list: C409874:7-methyl-6,7,8,9,14,15-hexahydro-5H-benz(d)indolo(2,3-g)azecine; D000475:Alkenes; D018492:Dopamine Antagonists; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D007211:Indoles; D008024:Ligands; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D002118:Calcium