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

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 D-1-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 ( K-i = 20-30 nM) for porcine D-1-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D-1 receptors but had much lower affinity at dopamine D-2-like receptors ( K-i = 3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D-1 agonist ligands around the beta-phenyldopamine pharmacophore template.