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

Dinapsoline ((2); (±)-dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline) is a full D₁ dopamine agonist that also has significant D₂ 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 D₁ agonist. Small alkyl substitutions on the dihydrexidine backbone are known to alter markedly the D₁:D₂ 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 D₁ affinity. Unexpectedly, and unlike the dihydrexidine series, these same substituents did not markedly increase D₂ affinity. The addition of a methyl group to position 6 (5) increased D₁:D₂ 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 D₁ affinity without affecting D₂ 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.