Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis

doi:10.1186/1471-2210-6-11

BMC Pharmacology

Volume 6

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Hamacher A
Weigt M
Wiese M
Hoefgen B
Lehmann J
Kassack MU

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Weigt M
Wiese M
Hoefgen B
Lehmann J
Kassack MU
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Research article

Dibenzazecine compounds with a novel dopamine/5HT_2Areceptor profile and 3D-QSAR analysis

Alexandra Hamacher¹ , Mathias Weigt¹ , Michael Wiese¹ , Barbara Hoefgen¹ , Jochen Lehmann² and Matthias U Kassack¹

¹Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany

²Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany

author email corresponding author email

BMC Pharmacology 2006, 6:11doi:10.1186/1471-2210-6-11


Published:	15 September 2006

Abstract

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-D₅and 5HT_2Areceptors and to assign them to different classes according to their dopamine/5HT_2Areceptor profile.

Results

Regardless of using affinity data (pK_ivalues at D₁-D₅and 5HT_2A) or selectivity data (15 log (K_iratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT_2Aligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of K_iratios used for principal component analysis from 15 to two (the D₁/D₂and D₂/5HT_2AK_iratios) 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 (D_2L> D₃> D_4.4) than clozapine (D_4.4> D_2L> D₃). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D₁selectivity.

Conclusion

In conclusion, two compounds with a novel dopamine/5HT_2Areceptor profile, LE404 and LE410, with some differences in their respective D₁/D₂receptor affinities including a validated pharmacophore-based 3D-QSAR model for D₁antagonists are presented.