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Probing structure-activity relationship in beta-arrestin2 recruitment of diversely substituted adenosine derivatives

(2018) BIOCHEMICAL PHARMACOLOGY. 158. p.103-113
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Abstract
In the adenosine receptor (AR) subfamily of G protein-coupled receptors (GPCRs), biased agonism has been described for the human AJAR, A(2B)AR and A(3)AR. While diverse A(3)AR agonists have been evaluated for receptor binding and G(i)-mediated cAMP signalling, the beta-arrestin2 (beta arr2) pathway has been left largely unexplored. We screened nineteen diverse adenosine derivatives for beta arr2 recruitment using a stable hA(3)AR-NanoBit(center dot)-beta arr2 HEK293T cell line. Their activity profiles were compared with a cAMP accumulation assay in stable hA(3)AR CHO cells. Structural features linked to beta arr2 activation were further investigated by the evaluation of an additional ten A(3)AR ligands. The A(3)AR-selective reference agonist 2-Cl-IB-MECA, which is a full agonist in terms of CAMP inhibition, only showed partial agonist behaviour in beta arr2 recruitment. Highly A(3)AR-selective (N)-methanocarba 5'-uronamide adenosine derivatives displayed higher potency in both cAMP signalling and beta arr2 recruitment than reference agonists NECA and 2-Cl-IB-MECA. Their A(3)AR-preferred conformation tolerates C2-position substitutions, for increased beta arr2 efficacy, better than the flexible scaffolds of ribose derivatives. The different amino functionalities in the adenosine scaffold of these derivatives each seem to be important for signalling as well. In conclusion, we have provided insights into ligand features that can help to guide the future therapeutic development of biased A3AR ligands with respect to G-protein and beta arr2 signalling.
Keywords
MU-OPIOID RECEPTOR, BIASED AGONISM, HEPATOCELLULAR-CARCINOMA, MEDICINAL, CHEMISTRY, A(3), NUCLEOSIDES, ACTIVATION, LIGANDS, POTENT, PAIN, G protein-coupled receptor, A(3) adenosine receptor, beta-arrestin2, Structure-activity relationship, Biased signaling

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Citation

Please use this url to cite or link to this publication:

MLA
Storme, Jolien et al. “Probing Structure-activity Relationship in Beta-arrestin2 Recruitment of Diversely Substituted Adenosine Derivatives.” BIOCHEMICAL PHARMACOLOGY 158 (2018): 103–113. Print.
APA
Storme, J., Tosh, D. K., Gao, Z.-G., Jacobson, K. A., & Stove, C. (2018). Probing structure-activity relationship in beta-arrestin2 recruitment of diversely substituted adenosine derivatives. BIOCHEMICAL PHARMACOLOGY, 158, 103–113.
Chicago author-date
Storme, Jolien, Dilip K Tosh, Zhan-Guo Gao, Kenneth A Jacobson, and Christophe Stove. 2018. “Probing Structure-activity Relationship in Beta-arrestin2 Recruitment of Diversely Substituted Adenosine Derivatives.” Biochemical Pharmacology 158: 103–113.
Chicago author-date (all authors)
Storme, Jolien, Dilip K Tosh, Zhan-Guo Gao, Kenneth A Jacobson, and Christophe Stove. 2018. “Probing Structure-activity Relationship in Beta-arrestin2 Recruitment of Diversely Substituted Adenosine Derivatives.” Biochemical Pharmacology 158: 103–113.
Vancouver
1.
Storme J, Tosh DK, Gao Z-G, Jacobson KA, Stove C. Probing structure-activity relationship in beta-arrestin2 recruitment of diversely substituted adenosine derivatives. BIOCHEMICAL PHARMACOLOGY. 2018;158:103–13.
IEEE
[1]
J. Storme, D. K. Tosh, Z.-G. Gao, K. A. Jacobson, and C. Stove, “Probing structure-activity relationship in beta-arrestin2 recruitment of diversely substituted adenosine derivatives,” BIOCHEMICAL PHARMACOLOGY, vol. 158, pp. 103–113, 2018.
@article{8604877,
  abstract     = {In the adenosine receptor (AR) subfamily of G protein-coupled receptors (GPCRs), biased agonism has been described for the human AJAR, A(2B)AR and A(3)AR. While diverse A(3)AR agonists have been evaluated for receptor binding and G(i)-mediated cAMP signalling, the beta-arrestin2 (beta arr2) pathway has been left largely unexplored. We screened nineteen diverse adenosine derivatives for beta arr2 recruitment using a stable hA(3)AR-NanoBit(center dot)-beta arr2 HEK293T cell line. Their activity profiles were compared with a cAMP accumulation assay in stable hA(3)AR CHO cells. Structural features linked to beta arr2 activation were further investigated by the evaluation of an additional ten A(3)AR ligands. The A(3)AR-selective reference agonist 2-Cl-IB-MECA, which is a full agonist in terms of CAMP inhibition, only showed partial agonist behaviour in beta arr2 recruitment. Highly A(3)AR-selective (N)-methanocarba 5'-uronamide adenosine derivatives displayed higher potency in both cAMP signalling and beta arr2 recruitment than reference agonists NECA and 2-Cl-IB-MECA. Their A(3)AR-preferred conformation tolerates C2-position substitutions, for increased beta arr2 efficacy, better than the flexible scaffolds of ribose derivatives. The different amino functionalities in the adenosine scaffold of these derivatives each seem to be important for signalling as well. In conclusion, we have provided insights into ligand features that can help to guide the future therapeutic development of biased A3AR ligands with respect to G-protein and beta arr2 signalling.},
  author       = {Storme, Jolien and Tosh, Dilip K and Gao, Zhan-Guo and Jacobson, Kenneth A and Stove, Christophe},
  issn         = {0006-2952},
  journal      = {BIOCHEMICAL PHARMACOLOGY},
  keywords     = {MU-OPIOID RECEPTOR,BIASED AGONISM,HEPATOCELLULAR-CARCINOMA,MEDICINAL,CHEMISTRY,A(3),NUCLEOSIDES,ACTIVATION,LIGANDS,POTENT,PAIN,G protein-coupled receptor,A(3) adenosine receptor,beta-arrestin2,Structure-activity relationship,Biased signaling},
  language     = {eng},
  pages        = {103--113},
  title        = {Probing structure-activity relationship in beta-arrestin2 recruitment of diversely substituted adenosine derivatives},
  url          = {http://dx.doi.org/10.1016/j.bcp.2018.10.003},
  volume       = {158},
  year         = {2018},
}

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