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Mapping the catechol binding site in dopamine D₁ receptors: synthesis and evaluation of two parallel series of bicyclic dopamine analogues. | LitMetric

AI Article Synopsis

  • - The study investigates a new class of isochroman dopamine analogues with over 100-fold selectivity for D₁-like receptors compared to D₂-like receptors, originally developed by Abbott Laboratories.
  • - Researchers found that changing the position of the oxygen atom in chroman compounds reduced their potency and shifted them towards D₂-like receptor selectivity due to potential intramolecular hydrogen bonding.
  • - Computational modeling and further experimentation demonstrated that removing the potential for this hydrogen bonding could restore the potency and selectivity for D₁-like receptors in these compounds.

Article Abstract

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. In silico 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515654PMC
http://dx.doi.org/10.1002/cmdc.201100010DOI Listing

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