ArticleChemMedChem2011
Mapping the catechol binding site in dopamine D₁ receptors: synthesis and evaluation of two parallel series of bicyclic dopamine analogues.
Article in ChemMedChem, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics.Current topics in medicinal chemistry · 2019Review
- Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson's disease.Asian journal of pharmaceutical sciences · 2018Review
- Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor.Nature communications · 2018Article
- Functional roles of T3.37 and S5.46 in the activation mechanism of the dopamine D1 receptor.Journal of molecular modeling · 2017Article
- Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes.Neural regeneration research · 2013Review
- Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands.ACS chemical neuroscience · 2013Article
- Parallel synthesis of 2-substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides.Molecules (Basel, Switzerland) · 2012Article
- Ligand-specific roles for transmembrane 5 serine residues in the binding and efficacy of dopamine D(1) receptor catechol agonists.Molecular pharmacology · 2012Article
- Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines.European journal of medicinal chemistry · 2012Article
- Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7α-, 7β-, 8α-, and 8β-methyl substituted dihydrexidine analogues.Journal of medicinal chemistry · 2011Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.