| Title
| - 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 D1Receptor Full Agonist
|
| Abstract
| - We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinolinehydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of thepotent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a keystep, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formationand reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involvedconjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed highaffinity (Ki = 20−30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity atcloned 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 constructingdopamine D1 agonist ligands around the β-phenyldopamine pharmacophore template.
|
