Evaluation of cis- and trans-9- and 11-hydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridines as structurally rigid, selective D1 dopamine receptor ligands

J Med Chem. 1995 Jan 20;38(2):318-27. doi: 10.1021/jm00002a013.


The present study reports the investigation of the D1 structure-relationships of certain cis- or trans-9- or 11-monohydroxy analogues of (+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine (8a, dihydrexidine), previously identified as the first full efficacy D1 dopamine receptor agonist. The monohydroxybenzo[a]phenanthridines were prepared from the appropriately substituted beta-tetralones using the methods described earlier for the synthesis of their catechol analogues. The 10-bromo 11-hydroxy derivative 9e was prepared by treatment of precursor 9c with bromine in chloroform. The affinities of these compounds for the D1 and D2 dopamine receptor classes and for their effects on adenylate cyclase activity were assessed in rat striatal membranes. In addition to producing only minimal increases in adenylate cyclase activity (< or = 15%), these phenolic derivatives generally had significantly lower affinities for D1 and D2 receptors (D1 IC50 > or = 102 nM, D2 IC50 > or = 210 nM) than did their catechol analogues. Further, compounds bearing a cis B/C-ring fusion displayed lower affinities than those bearing a trans configuration, paralleling the activity differences between the catechol analogues. The data for these rigid dopamine receptor ligands from the benzo[a]phenanthridine class lend additional support for the hypothesis that D1 agonist activity is optimized by a trans ring configuration that maintains the beta-phenyldopamine substructure in the "trans-beta-rotamer."

Publication types

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

MeSH terms

  • Animals
  • Binding, Competitive
  • Corpus Striatum / metabolism
  • Dopamine Agonists / chemical synthesis
  • Dopamine Agonists / chemistry*
  • Dopamine Antagonists / chemical synthesis
  • Dopamine Antagonists / chemistry*
  • Ligands
  • Male
  • Phenanthridines / chemistry*
  • Phenanthridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship


  • Dopamine Agonists
  • Dopamine Antagonists
  • Ligands
  • Phenanthridines