Mapping the catechol binding site in dopamine D1 receptors: Synthesis and evaluation of two parallel series of bicyclic dopamine analogues

Article abstract of DOI:10.1002/cmdc.201100010

A novel class of isochroman dopamine analogues, originally reported by Abbott Laboratories, have >100-fold selectivity for D₁-like over D₂-like receptors. We synthesized a parallel series of chroman compounds and showed that repositioning the oxygen atom in the heterocyclic ring decreases potency and confers D₂-like receptor selectivity to these compounds. Insilico modeling supports the hypothesis that the altered pharmacology for the chroman series is due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxy group of the catechol moiety. This interaction realigns the catechol hydroxy groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D₁-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds. Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D₁-like receptor potency and selectivity are restored. What a difference an H bond makes: Structurally related chromans, isochromans, and their carbocyclic analogues were assessed for dopamine D₁ and D₂ receptor affinity. Isochromans and carbocyclic analogues had high D₁ receptor affinity. Poor affinity for the chromans was attributed to an intramolecular hydrogen bond, which disrupts the ligand-receptor hydrogen bonding network.