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Chiroptical properties and conformational flexibility of fenoterol and analogues: a combined experimental and theoretical study
Get PDFFenoterol is a selective β 2 -adrenergic receptor (AR) agonist used in the treatment of asthma, which is
under scrutiny as possible drug against congestive heart failure. Fenoterol is currently used as a racemic
mixture of the (R,R′)- and (S,S′)-enantiomers, whose stereochemistry was previously determined by
electronic circular dichroism (ECD) analysis through the application of a semi-empirical sector rule. [1]
Recently, a series of fenoterol derivatives has been synthesized and tested: [2-3] their absolute
configuration was determined by chemical correlation with synthetic precursors, but no further
stereochemical characterization has been carried out. In addition, stereoselectivity in the binding to β 2 -
AR has been demonstrated, with (R,R′)- and (R,S′)-fenoterol displaying higher affinity compared to
(S,R′)- and (S,S′)-fenoterol, and a tridimensional quantitative structure-activity relationship model (3D-
QSAR) based on comparative molecular field analysis (CoMFA) has been developed to rationalize the
binding of fenoterol derivatives to β 2 -AR. [2-3]
The relationship between chiroptical properties and absolute stereochemistry of fenoterol and its
derivatives has been investigated [4] by experimental ECD analysis and quantum chemical (QC)
calculations using time-dependent density functional theory (TD-DFT). [5-6] The stereoisomers of three
compounds have been considered: fenoterol (1), (4′′-methoxy-1′′-naphthyl)fenoterol (2), and (4′′-methoxy-
1′-desmethyl)fenoterol (3). Due to the high conformational flexibility of the investigated structures and the
consequent large pool of equilibrium conformers, DFT geometry optimizations were carried out using the
resolution of identity (RI) approximation and the B97D functional with empirical dispersion corrections; [7]
TD-DFT calculations were then performed using the PBE0 functional. The accuracy of this protocol in
reproducing the experimental ECD spectra of fenoterol derivatives will be evaluated.
[1] F. Beigi, C. Bertucci, W. Zhu, K. Chakir, I.W. Wainer, R.P. Xiao, D.R. Abernethy, Chirality, 2006, 18, 822-827.
[2] K. Jóźwiak, K. Chakir, M.J. Tanga, I. Berzetei-Gurske, L. Jimenez, J.A. Kozocas, A. Woo, W. Zhu, R.P. Xiao,
D.R. Abernethy, I.W. Wainer, J. Med. Chem., 2007, 50, 2903-2915.
[3] K. Jóźwiak, A.Y.H. Woo, M.J. Tanga, L. Toll, L. Jimenez, J.A. Kozocas, A. Plazinska, R.P. Xiao, I.W. Wainer,
Bioorg. Med. Chem., 2010, 18, 728-736.
[4] ISCRA project IsC08_SCCFPM (ID: HP10CU0YHL) granted by CINECA, Bologna, Italy.
[5] J. Autschbach, Chirality, 2009, 21, E116-E152.
[6] L. Goerigk, H. Kruse, S. Grimme, in: N. Berova, P.L. Polavarapu, K. Nakanishi, R.W. Woody (Eds.),
Comprehensive chrioptical spectroscopy, vol. 1, 2011, Hoboken: Wiley & Sons, pp. 643-673.
[7] S. Grimme, WIREs Comput. Mol. Sci., 2011, 1, 211-228
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
sj-docx-3-aut-10.1177_13623613231195743 – Supplemental material for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda
No full textSupplemental material, sj-docx-3-aut-10.1177_13623613231195743 for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda by Katherine M Walton, Alayna R Borowy, Rachel A Gordon and Allison L Wainer in Autism</p
sj-docx-5-aut-10.1177_13623613231195743 – Supplemental material for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda
No full textSupplemental material, sj-docx-5-aut-10.1177_13623613231195743 for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda by Katherine M Walton, Alayna R Borowy, Rachel A Gordon and Allison L Wainer in Autism</p
sj-pdf-2-aut-10.1177_13623613231195743 – Supplemental material for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda
No full textSupplemental material, sj-pdf-2-aut-10.1177_13623613231195743 for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda by Katherine M Walton, Alayna R Borowy, Rachel A Gordon and Allison L Wainer in Autism</p
sj-pdf-1-aut-10.1177_13623613231195743 – Supplemental material for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda
No full textSupplemental material, sj-pdf-1-aut-10.1177_13623613231195743 for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda by Katherine M Walton, Alayna R Borowy, Rachel A Gordon and Allison L Wainer in Autism</p
sj-docx-4-aut-10.1177_13623613231195743 – Supplemental material for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda
No full textSupplemental material, sj-docx-4-aut-10.1177_13623613231195743 for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda by Katherine M Walton, Alayna R Borowy, Rachel A Gordon and Allison L Wainer in Autism</p
Stereochemical and conformational study on fenoterol by ECD spectroscopy and TD-DFT calculations
No full textFenoterol and its derivatives are selective β2-adrenergic receptor (β2-AR) agonists whose stereoselective biological activities have been extensively investigated in the past decade; a complete stereochemical characterization of fenoterol derivatives is therefore crucial for a better understanding of the effects of stereochemistry on β2-AR binding. In the present project, the relationship between chiroptical properties and absolute stereochemistry of the stereoisomers of fenoterol (1) was investigated by experimental ECD spectroscopy and time-dependent density functional theory (TD-DFT). DFT geometry optimizations were carried out at the RI-B97D/TZVP/IEFPCM(MeOH) level and subsequent TD-DFT calculations were performed using the PBE0 hybrid functional. Despite the large pool of equilibrium conformers found for the investigated compounds and the known limitations of the level of theory employed, the computational protocol was able to reproduce the experimental ECD spectra of the stereoisomers of 1. The main contribution to the overall chiroptical properties was found to arise from the absolute configuration of the chiral center in α-position to the resorcinol moiety. Based on this evidence, a thorough conformational analysis was performed on the optimized DFT conformers, which revealed the occurrence of a different equilibrium between conformational patterns for the diastereomers of fenoterol: the (R,R')/(S,S') enantiomeric pair showed a higher population of folded conformations than the (R,S')/(S,R') pair
sj-docx-6-aut-10.1177_13623613231195743 – Supplemental material for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda
No full textSupplemental material, sj-docx-6-aut-10.1177_13623613231195743 for Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda by Katherine M Walton, Alayna R Borowy, Rachel A Gordon and Allison L Wainer in Autism</p
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