916487-06-4Relevant articles and documents
Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines
Cueva, Juan Pablo,Chemel, Benjamin R.,Juncosa Jr., Jose I.,Lill, Markus A.,Watts, Val J.,Nichols, David E.
, p. 97 - 107 (2012)
Efforts to develop selective agonists for dopamine D1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric β-phenyldopamine-type full agonist ligands that display selectivity and potency at D1-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 D1- and D2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D1-like receptor binding, suggesting important differences between the interactions of these ligands with the D1 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.
trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: Synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist
Cueva, Juan Pablo,Giorgioni, Gianfabio,Grubbs, Russell A.,Chemel, Benjamin R.,Watts, Val J.,Nichols, David E.
, p. 6848 - 6857 (2007/10/03)
We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H- chromeno[3,4-c]isoquinoline hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the potent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high affinity (Ki = 20-30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D1 receptors but had much lower affinity at dopamine D2-like receptors (Ki = 3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the β-phenyldopamine pharmacophore template.
