ArticleMolecular pharmacology2015
Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound β1-Adrenergic Receptor.
Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Pooled it
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- G Protein-Coupled Receptor-Ligand Pose and Functional Class Prediction.International journal of molecular sciences · 2024Article
- Structures of Adrenoceptors.Handbook of experimental pharmacology · 2024Review
- Adrenoceptors: Receptors, Ligands and Their Clinical Uses, Molecular Pharmacology and Assays.Handbook of experimental pharmacology · 2024Review
- IUPHAR themed review: Opioid efficacy, bias, and selectivity.Pharmacological research · 2023Review
- A Novel "Activation Switch" Motif Common to All Aminergic Receptors.Journal of chemical information and modeling · 2023Review
- Ligands of Adrenergic Receptors: A Structural Point of View.Biomolecules · 2021Review
- Three-dimensional descriptors for aminergic GPCRs: dependence on docking conformation and crystal structure.Molecular diversity · 2019Article
- A benchmark study of loop modeling methods applied to G protein-coupled receptors.Journal of computer-aided molecular design · 2019Article
- Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine AStructure (London, England : 1993) · 2019Article
- Structural determinants of 5-HTNature structural & molecular biology · 2018Article
- In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease.Current neuropharmacology · 2018Article
- Insight into partial agonism by observing multiple equilibria for ligand-bound and GNature communications · 2017Article
- G protein-coupled receptors: the evolution of structural insight.AIMS biophysics · 2017Article
- A mutagenesis and screening strategy to generate optimally thermostabilized membrane proteins for structural studies.Nature protocols · 2016Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser(5.46), coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of β1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2-carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both β1AR and β2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey β1AR and an inverse agonist of human β2AR. The structure of 7-methylcyanopindolol-bound β1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound β1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol-bound β1AR and the hydroxyl group of Ser(5.46) is positioned 0.8 Å further from the ligand, with respect to the position of the Ser(5.46) side chain in cyanopindolol-bound β1AR. Thus, the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists.
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