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.
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.
Mohr
Patrick
P
Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany.
Decker
Michael
M
Enzensperger
Christoph
C
Lehmann
Jochen
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D011869:Radioligand Assay; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C509863:4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz(d,g)azecin-3-ol; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D050641:Receptors, Dopamine D5; D002118:Calcium