title: Dopamine/serotonin receptor ligands. Part VIII: the dopamine receptor antagonist LE300 - modelled and X-ray structure plus further pharmacological characterization, including serotonin receptor binding, biogenic amine transporter testing and in vivo testings.
abstract: -LE300, a benz[d]indolo[2,3-g]azecine with nanomolar affinities to the hD(1) receptor family, has been further pharmacologically characterized and its modelled structure was compared to its X-ray structure in order to explain NMR data, that was not in accordance to the X-ray structure. Moderate affinity at the hD(3) receptor was determined, nanomolar affinities were found at the 5-HT(2A) and 5-HT(2C) receptors, micromolar affinity at the 5-HT(1A) receptor using binding assays. Functional studies indicate moderate antagonist activity at the 5-HT(2A) site. No activity was found at dopamine, serotonin and norepinephrine transporters. These results suggested the use of LE300 for cocaine addiction treatment. High activities were found using in vivo testing: LE300 suppressed spontaneous locomotor activity with an ID(50) of 1.24 mg/kg and attenuated locomotor activity induced by 20 mg/kg cocaine with an AD(50) of 1.50 mg/kg. It failed to substitute for the discriminative stimulus effects produced by cocaine.
authors.affiliation: Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.forename: Klaus-Jürgen
authors.initials: KJ
authors.lastname: Schleifer
authors.forename: Martin
authors.initials: M
authors.lastname: Nieger
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019970:Cocaine-Related Disorders; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D026901:Membrane Transport Proteins / Q000378:metabolism; D009043:Motor Activity; D036103:Nanotechnology; D009638:Norepinephrine / Q000378:metabolism; D011485:Protein Binding; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014965:X-Rays
chemical_list: C409874:7-methyl-6,7,8,9,14,15-hexahydro-5H-benz(d)indolo(2,3-g)azecine; D001679:Biogenic Amines; D018492:Dopamine Antagonists; D007211:Indoles; D008024:Ligands; D026901:Membrane Transport Proteins; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D009638:Norepinephrine