Chiral indolo[3,2-f][3]benzazecine-type dopamine receptor antagonists: synthesis and activity of racemic and enantiopure derivatives

Dina Robaa; Christoph Enzensperger; Shams Eldin Abulazm; Mohamed M Hefnawy; Hussein I El-Subbagh; Tanveer A Wani; Jochen Lehmann

doi:10.1021/jm200676f

Chiral indolo[3,2-f][3]benzazecine-type dopamine receptor antagonists: synthesis and activity of racemic and enantiopure derivatives

J Med Chem. 2011 Oct 27;54(20):7422-6. doi: 10.1021/jm200676f. Epub 2011 Sep 29.

Authors

Dina Robaa¹, Christoph Enzensperger, Shams Eldin Abulazm, Mohamed M Hefnawy, Hussein I El-Subbagh, Tanveer A Wani, Jochen Lehmann

Affiliation

¹ Institut für Pharmazie, Abteilung Medizinische Chemie, Martin Luther Universität Halle-Wittenberg, Germany.

PMID: 21888437
DOI: 10.1021/jm200676f

Abstract

Racemic and enantiopure 8-substituted derivatives of the lead dopamine receptor antagonist LE 300 (1) were prepared, and their affinities for the dopamine receptors (D(1)-D(5)) were tested. The separate enantiomers showed significantly different affinities; the (8S)-methyl and (8R)-hyroxymethyl derivatives where the substituents point below the reference plane of the indolo[3,2-f][3]benzazecine scaffold were markedly more active than their enantiomeric counterparts. The racemic 8-carboxy derivative was shown to be selective for the D(5)-receptor, even against D(1).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CHO Cells
Cricetinae
Cricetulus
Dopamine Antagonists / chemical synthesis*
Dopamine Antagonists / chemistry
Dopamine Antagonists / pharmacology
HEK293 Cells
Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Radioligand Assay
Stereoisomerism
Structure-Activity Relationship

Substances

Dopamine Antagonists
Heterocyclic Compounds, 4 or More Rings
Indoles