Mapping the Catechol Binding Site in Dopamine D₁Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

Abstract

A novel class of isochroman dopamine analogues, 1, originally reported by Abbott Laboratories, had greater than 100-fold selectivity for D1-like vs. D2-like receptors. We synthesized a parallel series of chroman compounds, 2, and showed that repositioning the oxygen in the heterocyclic ring reduced potency and conferred D2-like receptor selectivity to these compounds. In silico modeling supported the hypothesis that the altered pharmacology for 2 was due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxyl of the catechol moiety. This interaction realigns the catechol hydroxyl 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, 3. Our results suggest that when the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity is restored.

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D1Receptor Catechol Agonists

“…These data suggest that the poor D 1 binding of the chromans is due, at least in part, to a detrimental effect of the heterocyclic oxygen atom when it is adjacent to the catechol ring. As proposed by Bonner et al (2011), this effect is probably due to an intramolecular hydrogen bond between the chroman oxygen and the m-OH, which may limit the ability of the catechol to interact productively with the TM5 serines.…”

“…This finding and the loss of D 1 -like receptor selectivity for the chroman among the unsubstituted bicyclic compounds (Bonner et al, 2011) underscore important differences between the structural requirements of D 1 -like and D 2 -like receptors. Unlike D 1 receptor ligands, many of the prototypical D 2 -like receptor full agonists are noncatechol (e.g., quinpirole), indicating that the catechol hydrogen bond requirements of D 2 receptors are less demanding.…”

“…These experiments were initially designed to explore the unexpected pharmacological profiles exhibited by structurally similar isochroman, chroman, and tetralin dopamine analogs (Bonner et al, 2011). Abbott Laboratories had developed bicyclic isochroman ligands with high-affinity and selectivity for D 1 -like receptors (DeNinno et al, 1991).…”

“…Encouraged by the creation of dinoxyline (Grubbs et al, 2004), an oxygen bioisostere of dinapsoline (Ghosh et al, 1996), we created the chroman analogs of the isochromans by repositioning the heterocyclic ring oxygen adjacent to the m-OH (Bonner et al, 2011). Surprisingly, this modification severely disrupted D 1 receptor affinity and selectivity of the chroman compounds.…”

Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT2A Serotonin Receptor Agonist Ligands

“…The synthesis of 6 then required only the reductive amination of omethoxybenzaldehyde with the brominated piperidine (21).…”