Evaluation of cis- and trans-9- and 11-Hydroxy-5, 6, 6a, 7, 8, 12b-hexahydrobenzo[α]phenanthridines as Structurally Rigid, Selective D₁ Dopamine Receptor Ligands

The present study reports the investigation of the D₁ structure-relationships of certain cis- or trans-9- or 11-monohydroxy analogues of (±)-trαns-10,11-dihydroxy-5, 6, 6a, 7, 8, 12b-hexahydrobenzo[α]phenanthridine (8a, dihydrexidine), previously identified as the first full efficacy D₁ dopamine receptor agonist. The monohydroxybenzo[α]phenanthridines were prepared from the appropriately substituted β-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 (≤15%), these phenolic derivatives generally had significantly lower affinities for D₁ and D₂ receptors (D₁ IC₅₀ ≥ 102 nM, D₂ IC₅₀ ≥ 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[α]phenanthridine class lend additional support for the hypothesis that Di agonist activity is optimized by a trans ring configuration that maintains the β-phenyldopamine substructure in the “trans-β-rotamer”.