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Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

European Journal of Medicinal Chemistry

By:
, , , , ,
DOI: 10.1016/j.ejmech.2011.11.039

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Abstract

Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.

Additional Publication Details

Publication type:
Article
Publication Subtype:
Journal Article
Title:
Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines
Series title:
European Journal of Medicinal Chemistry
DOI:
10.1016/j.ejmech.2011.11.039
Volume
48
Year Published:
2012
Language:
English
Larger Work Type:
Article
Larger Work Subtype:
Journal Article
First page:
97
Last page:
107
Number of Pages:
11