Synthesis and Evaluation of 6,7-Dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 6,7-Dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, and 10-(Aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene as Conformationally Restricted Analogs of β-Phenyldopamine

The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D₁ receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D₁ agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D₁ and D₂ dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D₁ receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.