Synthesis and pharmacological evaluation of substituted naphth[1,2,3-de]isoquinolines (dinapsoline analogues) as D1 and D2 dopamine receptor ligands

Bioorg Med Chem. 2003 Apr 3;11(7):1451-64. doi: 10.1016/s0968-0896(02)00561-8.

Abstract

Dinapsoline ((2); (+/-)-dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline) is a full D(1) dopamine agonist that also has significant D(2) receptor affinity. Based on a similar pharmacophore, dinapsoline has pharmacological similarities to dihydrexidine ((1); (+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine), the first high affinity full D(1) agonist. Small alkyl substitutions on the dihydrexidine backbone are known to alter markedly the D(1):D(2) selectivity of dihydrexidine, and it was of interest to determine whether similar SAR exists within the dinapsoline series. This report describes the synthesis and pharmacological evaluation of six analogues of dinapsoline: N-allyl-(3);N-n-propyl- (4); 6-methyl- (5); 4-methyl- (6); 4-methyl-N-allyl- (7); and 4-methyl-N-n-propyl-dinapsoline (8). As expected from earlier studies with the dihydrexidine backbone, N-allyl (3) or N-n-propyl (4) analogues had markedly decreased D(1) affinity. Unexpectedly, and unlike the dihydrexidine series, these same substituents did not markedly increase D(2) affinity. The addition of a methyl group to position 6 (5) increased D(1):D(2) selectivity, but less markedly than did the analogous 2-methyl substituent added to 1. Unlike the analogous 4-methyl substituent of 1, the addition of a 4-methyl-group (6) actually decreased D(1) affinity without affecting D(2) affinity. These data demonstrate that the dinapsoline (2) backbone can be modified to produce dopamine agonists with novel properties. Moreover, as rigid ligands in which small substituents can cause significant changes in selectivity, they are important tools for deriving 'differential' SARs of the dopamine receptor isoforms.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Neoplasms / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cloning, Molecular
  • Cyclic AMP / biosynthesis
  • Cyclization
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / pharmacology*
  • Glioma / metabolism
  • In Vitro Techniques
  • Indicators and Reagents
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology*
  • Naphthols / chemical synthesis*
  • Naphthols / pharmacology*
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Dopamine D1 / agonists*
  • Receptors, Dopamine D2 / agonists*
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Dopamine Agonists
  • Indicators and Reagents
  • Isoquinolines
  • Naphthols
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Recombinant Proteins
  • dinapsoline
  • Cyclic AMP