(+)-Dinapsoline: an efficient synthesis and pharmacological profile of a novel dopamine agonist

J Med Chem. 2002 Aug 15;45(17):3660-8. doi: 10.1021/jm0101545.

Abstract

A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).

MeSH terms

  • Animals
  • Cell Line
  • Corpus Striatum / metabolism
  • Crystallography, X-Ray
  • Cyclic AMP / biosynthesis
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / pharmacology
  • In Vitro Techniques
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology
  • Molecular Conformation
  • Naphthols / chemical synthesis*
  • Naphthols / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Stereoisomerism

Substances

  • Dopamine Agonists
  • Isoquinolines
  • Naphthols
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • dinapsoline
  • Cyclic AMP