Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis.
BACKGROUND
Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D1-D5 and 5HT2A receptors and to assign them to different classes according to their dopamine/5HT2A receptor profile.


RESULTS
Regardless of using affinity data (pKi values at D1-D5 and 5HT2A) or selectivity data (15 log (Ki ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT2A ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of Ki ratios used for principal component analysis from 15 to two (the D1/D2 and D2/5HT2A Ki ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D2-like receptor profile (D2L > D3 > D4.4) than clozapine (D4.4 > D2L > D3). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D1 selectivity.


CONCLUSIONS
In conclusion, two compounds with a novel dopamine/5HT2A receptor profile, LE404 and LE410, with some differences in their respective D1/D2 receptor affinities including a validated pharmacophore-based 3D-QSAR model for D1 antagonists are presented.
Hamacher
Alexandra
A
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. alexhamacher@web.de
Weigt
Mathias
M
Wiese
Michael
M
Hoefgen
Barbara
B
Lehmann
Jochen
J
Kassack
Matthias U
MU
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003984:Dibenzazepines / Q000737:chemistry* / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D021281:Quantitative Structure-Activity Relationship; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism
C508806:7-methyl-2,3-dimethoxy-5,6,7,8,9,14-hexahydrodibenz(d,g)azecine; D003984:Dibenzazepines; D018492:Dopamine Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D044402:Receptor, Serotonin, 5-HT2A; D011954:Receptors, Dopamine; D012702:Serotonin Antagonists