Dopamine/Serotonin Receptor Ligands. 13: Homologization of a Benzindoloazecine-Type Dopamine Receptor Antagonist Modulates the Affinities for Dopamine D₁−D₅ Receptors

Enlarging the 10-membered ring of 7-methyl-6,7,8,9,14,15-hexahydro-5H-indolo[3,2-f][3]benzazecine (1, LE 300) yielded two homologue antagonists. Their affinities and inhibitory activities at D1−D5 receptors were measured by radioligand binding experiments and a functional Ca2+ assay. Compared to 1, phenylpropyl homologue 3 was superior in selectivity and affinity for the D5 subtype (Ki = 0.6 nM), whereas the affinity of the indolylpropyl homologue 2 for all subtypes decreased. Compounds 2, 3, 10, 11, 17, and 18 are derivatives of novel heterocyclic ring systems

Dopamine/Serotonin Receptor Ligands. 12: SAR Studies on Hexahydro-dibenz[<i>d</i>,<i>g</i>]azecines Lead to 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[<i>d,g</i>]azecin-3-ol, the First Picomolar D₅-Selective Dopamine-Receptor Antagonist

Hydroxylated, methoxylated, and/or chlorinated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines were generally synthesized out of substituted 2-phenylethylamines and isochromanones by Bischler−Napieralski cyclization of the resulting benzamides to dibenzoquinolizines and the quaternization and cleavage of the central C−N bond under Birch conditions. Chlorination of 2-phenylethylamines was useful for the site direction of cyclization, but chlorine atoms were removed under Birch conditions so that chlorination had to be repeated to get the respective chlorinated dibenz[d,g]azecines. The target compounds were tested for their affinity at the different human-cloned dopamine-receptor subtypes (D1 family, D2 family). Generally, hydroxylation and chlorination of the dibenz-azecines increased affinities significantly. 1-Chloro-2-hydroxy-hexahydro-dibenz[d,g]azecine was a subnanomolar antagonist at both subtype families. 4-Chloro-3-hydroxy-7-methyl-5,6,7,8,9,14-hexahydro-dibenz[d,g]azecine was identified as the most potent and selective dopamine D5 receptor ligand described to date with Ki(D1) = 0.83, Ki(D2L) = 4.0, Ki(D3) = 24.6, Ki(D4) = 5.2 nM, and Ki(D5) = 57 pM (radioligand binding experiments), respectively

Dopamine/Serotonin Receptor Ligands. 12: SAR Studies on Hexahydro-dibenz[<i>d</i>,<i>g</i>]azecines Lead to 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[<i>d,g</i>]azecin-3-ol, the First Picomolar D₅-Selective Dopamine-Receptor Antagonist

Hydroxylated, methoxylated, and/or chlorinated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines were generally synthesized out of substituted 2-phenylethylamines and isochromanones by Bischler−Napieralski cyclization of the resulting benzamides to dibenzoquinolizines and the quaternization and cleavage of the central C−N bond under Birch conditions. Chlorination of 2-phenylethylamines was useful for the site direction of cyclization, but chlorine atoms were removed under Birch conditions so that chlorination had to be repeated to get the respective chlorinated dibenz[d,g]azecines. The target compounds were tested for their affinity at the different human-cloned dopamine-receptor subtypes (D1 family, D2 family). Generally, hydroxylation and chlorination of the dibenz-azecines increased affinities significantly. 1-Chloro-2-hydroxy-hexahydro-dibenz[d,g]azecine was a subnanomolar antagonist at both subtype families. 4-Chloro-3-hydroxy-7-methyl-5,6,7,8,9,14-hexahydro-dibenz[d,g]azecine was identified as the most potent and selective dopamine D5 receptor ligand described to date with Ki(D1) = 0.83, Ki(D2L) = 4.0, Ki(D3) = 24.6, Ki(D4) = 5.2 nM, and Ki(D5) = 57 pM (radioligand binding experiments), respectively

Dopamine/Serotonin Receptor Ligands. 16. Expanding Dibenz[<i>d,g</i>]azecines to 11- and 12-Membered Homologues. Interaction with Dopamine D₁−D₅ Receptors

Oxygenated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are potent dopamine receptor antagonists, preferentially at D1/D5. We synthesized the hydroxylated, methoxylated, and chlorinated 11-membered and 12-membered homologues of these 10-membered heterocycles. Their affinities for the human cloned D1−D5 receptors (radioligand binding) and functionalities (calcium assay) were measured. Enlarging the dibenzazecines to the corresponding dibenzazacycloundecenes and dibenzazacyclododecenes generally maintains the high antagonistic affinity for D1/D5 but also leads to a compound with a clozapine-like binding profile due to additional affinity for D4

Dopamine Receptor Ligands. Part 18: Modification of the Structural Skeleton of Indolobenzazecine-Type Dopamine Receptor Antagonists

On the basis of the D1/5-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca2+ assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f]benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities

Chiral Indolo[3,2-<i>f</i>][3]benzazecine-Type Dopamine Receptor Antagonists: Synthesis and Activity of Racemic and Enantiopure Derivatives

Racemic and enantiopure 8-substituted derivatives of the lead dopamine receptor antagonist LE 300 (1) were prepared, and their affinities for the dopamine receptors (D1–D5) were tested. The separate enantiomers showed significantly different affinities; the (8S)-methyl and (8R)-hyroxymethyl derivatives where the substituents point below the reference plane of the indolo[3,2-f][3]benzazecine scaffold were markedly more active than their enantiomeric counterparts. The racemic 8-carboxy derivative was shown to be selective for the D5-receptor, even against D1

Evaluation of Homobivalent Carbolines as Designed Multiple Ligands for the Treatment of Neurodegenerative Disorders

Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-carbolinium salts as potent inihitors of both cholinesterases, <i>N</i>-methyl-d-aspartate receptors, and monoamine oxidases. Homobivalent γ-carbolines displayed similar structure–activity relationships on all tested targets and may present promising designed multiple ligands for the treatment of neurodegenerative disorders

Evaluation of Homobivalent Carbolines as Designed Multiple Ligands for the Treatment of Neurodegenerative Disorders

Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-carbolinium salts as potent inihitors of both cholinesterases, <i>N</i>-methyl-d-aspartate receptors, and monoamine oxidases. Homobivalent γ-carbolines displayed similar structure–activity relationships on all tested targets and may present promising designed multiple ligands for the treatment of neurodegenerative disorders