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

• Published in: Archiv der Pharmazie (Weinheim) 2002-11, Vol.335 (8), p.367-373
• Main Authors: Abadi, Ashraf H., Lankow, Stefan, Hoefgen, Barbara, Decker, Michael, Kassack, Matthias U., Lehmann, Jochen
• Format: Article
• Language: English
• Subjects: 3-g]azecines; Algorithms; Alkenes - chemical synthesis; Alkenes - pharmacology; Benz[d]indolo; Benz[d]indolo[2, 3‐g]azecines; Binding, Competitive - drug effects; Biological and medical sciences; Bivalent ligand approach; Calcium - metabolism; Calcium assay; Catecholaminergic system; Cell Line; Dopamine antagonists; Dopamine Antagonists - chemical synthesis; Dopamine Antagonists - pharmacology; Fluorescent Dyes; Humans; Indicators and Reagents; Indoles - chemical synthesis; Indoles - pharmacology; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Quinolizine cleavage; Radioligand binding; Receptors, Dopamine - drug effects; Receptors, Dopamine D1 - drug effects; Receptors, Dopamine D2 - drug effects; Receptors, Serotonin - drug effects
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/1521-4184(200211)335:8<367::AID-ARDP367>3.0.CO;2-C

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 D1 and D2 receptors were estimated by radioligand binding and a functional Ca2+ assay. All the new bivalent ligands showed significant binding affinities to both D1 and D2 receptorswith an optimal distance between the two monomeric recognition unitsof 6 methylene moieties. The D1/D2‐selectivity pattern was dependent on the spacer length. No (7a, b) or only moderate (7c—e) functional activity wasdetected for all bivalent compounds by measuring the inhibition of agonist‐induced increase in intracellular Ca2+.