Citation/Abstract

To gain a better understanding of the structural and conformational features that enable selective activation of the dopamine D ₁ receptor by β-phenyldopamine-type ligands, a series of compounds was prepared and tested for their D ₁ - and D ₂ -like receptor affinities and for their ability to induce receptor activation. A new synthesis of the known D ₁ -selective ligand dihydrexidine has been developed and modified to allow preparation of substituted hexahydrobenzo[ a ]phenanthridines. This novel approach allowed the synthesis of dihydrexidine analogs substituted with methyl groups on the 7-position, leading to the discovery that the D ₁ and D ₂ receptors have no tolerance for substitutions in this region of the ligand. Replacement of the 8-methylene of dihydrexidine with an oxygen atom led to a new molecule that had dramatically increased selectivity and which was named doxanthrine. Extension of the SAR of these novel chromanoisoquinolines by substitutions on the β-phenyl ring revealed key differences between the interaction of this template and the hexahydrobenzo[ a ]phenanthridines with the D ₁ receptor binding site. Investigation of the preferred conformation of the β-phenyl ring was carried out by examining the D ₁ receptor affinities of a ring-expanded analog of doxanthrine and a rigid analog of SKF38393, suggesting that deviation from coplanarity of this substituent appears to be necessary to achieve high affinity D ₁ binding. Overall, these studies have led to further improvements in our understanding of the functional topography of the dopamine D ₁ receptor.