Synthesis and Biological Evaluation of a Series of Substituted Benzo[α]phenanthridines as Agonists at D₁ and D₂ Dopamine Receptors

Dihydrexidine [4; (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (DHX)], the first high-affinity full D₁ agonist, also is known to have significant D₂ activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (±)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (5) was a high-affmity D₁ agonist, having approximately 4-fold greater D₁ vs D₂ selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D₁ receptor. It is apparent from these results that the D₁ receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D₂ selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D₂ receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D₁ and D₂ receptors. It was subsequently established that this compound is a selective D₃ ligand (110-fold selectivity for the D₃ over D₂ receptor). The results from these studies demonstrate that several of the hexahydrobenzo[α]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D₂ receptor) of drugs for D₁ receptors.