Dibenzazecine compounds with a novel dopamine/5HT(2A )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 D(1)-D(5 )and 5HT(2A )receptors and to assign them to different classes according to their dopamine/5HT(2A )receptor profile. RESULTS: Regardless of using affinity data (pK(i )values at D(1)-D(5 )and 5HT(2A)) or selectivity data (15 log (K(i )ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT(2A )ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of K(i )ratios used for principal component analysis from 15 to two (the D(1)/D(2 )and D(2)/5HT(2A )K(i )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 D(2)-like receptor profile (D(2L )> D(3 )> D(4.4)) than clozapine (D(4.4 )> D(2L )> D(3)). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D(1 )selectivity. CONCLUSION: In conclusion, two compounds with a novel dopamine/5HT(2A )receptor profile, LE404 and LE410, with some differences in their respective D(1)/D(2 )receptor affinities including a validated pharmacophore-based 3D-QSAR model for D(1 )antagonists are presented.