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 D-1 receptor full agonist

We report the synthesis and resolution of the enantiomers of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4 c]¬isoquinoline hydrochloride 6. 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) and full intrinsic activity at cloned human dopamine D1 receptors, and for porcine D1–like receptors in native striatal tissue, but had much lower activity at dopamine D2 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.