Dopamine/serotonin receptor ligands. 12(1): SAR studies on hexahydro-dibenz[d,g]azecines lead to 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol, the first picomolar D5-selective dopamine-receptor antagonist.

doi:10.1021/JM051237E

Paper

Dopamine/serotonin receptor ligands. 12(1): SAR studies on hexahydro-dibenz[d,g]azecines lead to 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol, the first picomolar D5-selective dopamine-receptor antagonist.

Published Feb 17, 2006 · P. Mohr, M. Decker, C. Enzensperger

Journal of medicinal chemistry

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38

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0

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Abstract

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.

Study Snapshot

4-Chloro-3-hydroxy-7-methyl-5,6,7,8,9,14-hexahydro-dibenz[d,g]azecine is the most potent and selective dopamine D5 receptor ligand to date, with a Ki(D1) of 0.83 and a Ki

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Dopamine/serotonin receptor ligands. 12(1): SAR studies on hexahydro-dibenz[d,g]azecines lead to 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol, the first picomolar D5-selective dopamine-receptor antagonist.

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Citations

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