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

J Med Chem. 2006 Nov 16;49(23):6848-57. doi: 10.1021/jm0604979.

Abstract

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 beta-phenyldopamine pharmacophore template.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Binding, Competitive
  • Cell Line
  • Corpus Striatum / metabolism
  • Crystallography, X-Ray
  • Cyclic AMP / biosynthesis
  • Humans
  • In Vitro Techniques
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Molecular Structure
  • Phenanthridines / chemical synthesis*
  • Phenanthridines / chemistry
  • Phenanthridines / pharmacology
  • Psychotropic Drugs / chemical synthesis*
  • Psychotropic Drugs / chemistry
  • Psychotropic Drugs / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Dopamine D1 / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine

Substances

  • 2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno(3,4-c)isoquinoline
  • Benzopyrans
  • Isoquinolines
  • Phenanthridines
  • Psychotropic Drugs
  • Receptors, Dopamine D1
  • dihydrexidine
  • Cyclic AMP