The role of kinetic context in apparent biased agonism at GPCRs

Nature Communications

Volumn 7, Issue , 2016, Pages

  Herenbrink, Carmen Klein ^a   Sykes, David A ^b   Donthamsetti, Prashant ^c   Canals, Meritxell ^a   Coudrat, Thomas ^a   Shonberg, Jeremy ^a   Scammells, Peter J ^a   Capuano, Ben ^a   Sexton, Patrick M ^a   Charlton, Steven J ^b   Javitch, Jonathan A ^c,d   Christopoulos, Arthur ^a   Lane, J Robert ^a  

^a MONASH UNIVERSITY   (Australia)

^b UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^c Columbia University ^*  (United States)

^d NEW YORK STATE PSYCHIATRIC INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOTENSIN RECEPTOR; ARIPIPRAZOLE; BETA ARRESTIN 2; BIFEPRUNOX; CARIPRAZINE; CYCLIC AMP; DOPAMINE; DOPAMINE 2 RECEPTOR STIMULATING AGENT; G PROTEIN COUPLED RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; PARDOPRUNOX; PRECLAMOL; ROPINIROLE; DOPAMINE 2 RECEPTOR; DOPAMINE RECEPTOR STIMULATING AGENT; INDOLE DERIVATIVE; LIGAND; PIPERAZINE DERIVATIVE; PIPERIDINE DERIVATIVE;

DRUG; EXPERIMENTAL DESIGN; LIGAND; PROTEIN; REACTION KINETICS; TEMPORAL ANALYSIS;

ANIMAL CELL; ARTICLE; BINDING KINETICS; BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; CHO CELL LINE; DESENSITIZATION; DISSOCIATION; DOSE RESPONSE; DRUG RECEPTOR BINDING; ENZYME PHOSPHORYLATION; FEMALE; INTRACELLULAR SIGNALING; LIGAND BINDING; NONHUMAN; SIGNAL TRANSDUCTION; AGONISTS; ANIMAL; CRICETULUS; KINETICS; METABOLISM; PRINCIPAL COMPONENT ANALYSIS; PROTEIN STABILITY;

ANIMALS; ARIPIPRAZOLE; CHO CELLS; CRICETULUS; DOPAMINE; DOPAMINE AGONISTS; INDOLES; KINETICS; LIGANDS; PIPERAZINES; PIPERIDINES; PRINCIPAL COMPONENT ANALYSIS; PROTEIN STABILITY; RECEPTORS, DOPAMINE D2;

EID: 84959421117     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms10842     Document Type: Article

References (64)

1. Whalen, E. J., Rajagopal, S. & Lefkowitz, R. J. Therapeutic potential of b-Arrestin- and G protein-biased agonists. Trends Mol. Med. 17, 126-139 (2011
2. Kenakin, T. & Christopoulos, A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discov. 12, 205-216 (2013
3. Urban, J. D., et al. Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320, 1-13 (2007
4. Overington, J. P., Al-Lazikani, B. & Hopkins, A. L. How many drug targets are there? Nat. Rev. Drug Discov. 5, 993-996 (2006
5. Violin, J. D., Crombie, A. L., Soergel, D. G. & Lark, M. W. Erratum: biased ligands at G protein-coupled receptors: promise and progress. Trends Pharmacol. Sci. 35, 308-316 (2014
6. Wisler, J. W., et al. A unique mechanism of beta-blocker action: carvedilol stimulates beta-Arrestin signaling. Proc. Natl Acad. Sci. 104, 16657-16662 (2007
7. Drake, M. T., et al. beta-Arrestin-biased agonism at the beta2-Adrenergic receptor. J. Biol. Chem. 283, 5669-5676 (2008
8. Galandrin, S. & Bouvier, M. Distinct signaling profiles of beta1 and beta2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-Activated protein kinase reveals the pluridimensionality of efficacy. Mol. Pharmacol. 70, 1575-1584 (2006
9. Rajagopal, S., et al. Quantifying ligand bias at seven-Transmembrane receptors. Mol. Pharmacol. 80, 367-377 (2011
10. Kenakin, T., Watson, C., Muniz-Medina, V., Christopoulos, A. & Novick, S. A simple method for quantifying functional selectivity and agonist bias. ACS Chem. Neurosci. 3, 193-203 (2012
11. Griffin, M., Figueroa, K., Liller, S. & Ehlert, F. Estimation of agonist activity at G protein-coupled receptors: analysis of M2 muscarinic receptor signaling through Gi/o, Gs, and G15. J. Pharmacol. Exp. Ther. 321, 1193-1207 (2007
12. Black, J. W. & Leff, P. Operational models of pharmacological agonism. Proc. R. Soc. Lond. B. Biol. Sci. 220, 141-162 (1983
13. Shonberg, J., et al. Biased agonism at G protein-coupled receptors: the promise and the challenges-A medicinal chemistry perspective. Med. Res. Rev. 34, 1286-1330 (2014
14. Urban, J. D., Vargas, G. a., von Zastrow, M. & Mailman, R. B. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology 32, 67-77 (2007
15. Allen, J., et al. Discovery of b-Arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc. Natl Acad. Sci. USA 108, 18488-18493 (2011
16. Masri, B., et al. Antagonism of dopamine D2 receptor/beta-Arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc. Natl Acad. Sci. USA 105, 13656-13661 (2008
17. Szabo, M., Klein Herenbrink, C., Christopoulos, A., Lane, J. R. & Capuano, B. Structure-Activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine d2 receptor. J. Med. Chem. 57, 4924-4939 (2014
18. Tschammer, N., Bollinger, S., Kenakin, T. & Gmeiner, P. Histidine 6.55 is a major determinant of ligand-biased signaling in dopamine D2L receptor. Mol. Pharmacol. 79, 575-585 (2011
19. Sheth, H., Gorey, C. & Roush, N. A multiplexed fluorescent calcium and NFAT reporter gene assay to identify GPCR agonists. Curr. Chem. Genomics Transl. Med. 7, 1-8 (2013
20. Mackay, D. A critical survey of receptor theories of drug action. Kinet. Drug Action 225-321 (1977
21. Agid, O., Kapur, S. & Remington, G. Emerging drugs for schizophrenia. Expert Opin. Emerg. Drugs 13, 479-495 (2008
22. Durgam, S., et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr. Res. 152, 450-457 (2014
23. Lahti, A., et al. Antipsychotic properties of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-Nn-propylpiperidine (preclamol) in schizophrenia. Biol. Psychiatry 43, 2-11 (1998
24. Sampaio, C., et al. Pardoprunox in early Parkinson's disease: results from 2 large, randomized double-blind trials. Mov. Disord. 26, 1464-1476 (2011
25. Gazi, L., Nickolls, S. A. & Strange, P. G. Functional coupling of the human dopamine D2 receptor with G alpha i1, G alpha i2, G alpha i3 and G alpha o G proteins: evidence for agonist regulation of G protein selectivity. Br. J. Pharmacol. 138, 775-786 (2003
26. Lane, J. R., Powney, B., Wise, A., Rees, S. & Milligan, G. Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an agonist for activation of Go1 but an antagonist/inverse agonist for Gi1, Gi2, and Gi3. Mol. Pharmacol. 71, 1349-1359 (2007
27. Stallaert, W., Dorn, J., Van Der Westhuizen, E., Audet, M. & Bouvier, M. Impedance responses reveal b2-Adrenergic receptor signaling pluridimensionality and allow classification of ligands with distinct signaling profiles. PLoS ONE 7, 1-14 (2012
28. Abdi, H. & Williams, L. J. Principal component analysis. Wiley Interdiscip. Rev. Comput. Stat. 2, 433-459 (2010
29. Charlton, S. J. & Vauquelin, G. Elusive equilibrium: the challenge of interpreting receptor pharmacology using calcium assays. Br. J. Pharmacol. 161, 1250-1265 (2010
30. Guo, D., Mulder-Krieger, T., IJzerman, A. P. & Heitman, L. H. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time. Br. J. Pharmacol. 166, 1846-1859 (2012
31. Motulsky, H. & Mahan, L. The kinetics of competitive radioligand binding predicted by the law of mass action. Mol. Pharmacol. 25, 1-9 (1984
32. Sykes, D., Dowling, M. & Charlton, S. Exploring the mechanism of agonist efficacy: a relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor. Mol. Pharmacol. 76, 543-551 (2009
33. Sibley, D. R., Mahan, L. C. & Creese, I. Dopamine receptor binding on intact cells. Absence of a high-Affinity agonist-receptor binding state. Mol. Pharmacol. 23, 295-302 (1983
34. Tummino, P. & Copeland, R. Residence time of receptor- ligand complexes and its effect on biological function. Biochemistry 47, 5481-5492 (2008
35. Vilums, M., et al. Structure-kinetic relationships-An overlooked parameter in hit-To-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists. J. Med. Chem. 56, 7706-7714 (2013
36. Ahn, S., Shenoy, S. K., Wei, H. & Lefkowitz, R. J. Differential kinetic and spatial patterns of beta-Arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J. Biol. Chem. 279, 35518-35525 (2004
37. Shenoy, S. K., et al. beta-Arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J. Biol. Chem. 281, 1261-1273 (2006
38. Liu, J. J., Horst, R., Katritch, V., Stevens, R. C. & Wüthrich, K. Biased signaling pathways in b2-Adrenergic receptor characterized by 19F-NMR. Science 335, 1106-1110 (2012
39. Warne, T., Edwards, P., Leslie, A. & Tate, C. Crystal structures of a stabilized b 1-Adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure 20, 841-849 (2012
40. Rahmeh, R., et al. Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc. Natl Acad. Sci. USA 109, 6733-6738 (2012
41. Kahsai, A. W., et al. Multiple ligand-specific conformations of the b2-Adrenergic receptor. Nat. Chem. Biol. 7, 692-700 (2011
42. Wacker, D., et al. Structural features for functional selectivity at serotonin receptors. Science 340, 615-619 (2013
43. Van Der Westhuizen, E. T., Breton, B., Christopoulos, A. & Bouvier, M. Quantification of ligand bias for clinically relevant b2-Adrenergic receptor ligands: implications for drug taxonomy. Mol. Pharmacol. 85, 492-509 (2014
44. McPherson, J., et al. M-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol. Pharmacol. 78, 756-766 (2010
45. Molinari, P., et al. Morphine-like opiates selectively antagonize receptor-Arrestin interactions. J. Biol. Chem. 285, 12522-12535 (2010
46. Kilpatrick, G. J., et al. The thermodynamics of agonist and antagonist binding to dopamine D-2 receptors. Mol. Pharmacol. 30, 226-234 (1986
47. Vilardaga, J. P., Jean-Alphonse, F. G. & Gardella, T. J. Endosomal generation of cAMP in GPCR signaling. Nat. Chem. Biol. 10, 700-706 (2014
48. Unett, D., Gatlin, J. & Anthony, T. Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration. J. Pharmacol. Exp. Ther. 347, 645-659 (2013
49. Möller, D., Kling, R. & Skultety, M. Functionally selective dopamine D2, D3 receptor partial agonists. J. Med. Chem. 57, 4861-4875 (2014
50. Chen, X.-T., et al. Structure-Activity relationships and discovery of a G protein biased m opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J. Med. Chem. 56, 8019-8031 (2013
51. Nijmeijer, S., Vischer, H. F., Rosethorne, E. M., Charlton, S. J. & Leurs, R. Analysis of multiple histamine H4 receptor compound classes uncovers g i protein- and -Arrestin2-biased ligands. Mol. Pharmacol. 82, 1174-1182 (2012
52. Shonberg, J., et al. A structure-Activity analysis of biased agonism at the dopamine D2 receptor. J. Med. Chem. 56, 9199-9221 (2013
53. Murphy, J. E., Padilla, B. E., Hasdemir, B., Cottrell, G. S. & Bunnett, N. W. Endosomes: a legitimate platform for the signaling train. Proc. Natl Acad. Sci. USA 106, 17615-17622 (2009
54. Irannejad, R., et al. Conformational biosensors reveal GPCR signalling from endosomes. Nature 495, 534-538 (2013
55. Ferrandon, S., et al. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat. Chem. Biol. 5, 734-742 (2009
56. Sykes, D. A., et al. Investigating the molecular mechanisms through which FTY720-P causes persistent S1P1 receptor internalization. Br. J. Pharmacol. 171, 4797-4807 (2014
57. Andreassen, K. V., et al. Prolonged calcitonin receptor signaling by salmon, but not human calcitonin, reveals ligand bias. PLoS ONE 9, e92042 (2014
58. Carboni, L., et al. Slow dissociation of partial agonists from the D2 receptor is linked to reduced prolactin release. Int. J. Neuropsychopharmacol. 15, 645-656 (2012
59. Saulière, A., et al. Deciphering biased-Agonism complexity reveals a new active AT1 receptor entity. Nat. Chem. Biol. 8, 622-630 (2012
60. Akinc, A., Thomas, M., Klibanov, A. M. & Langer, R. Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J. Gene Med. 7, 657-663 (2005
61. Cheng, Y. & Prusoff, W. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099-3108 (1973
62. Kenakin, T., Watson, C., Muniz-Medina, V., Christopoulos, A. & Novick, S. A simple method for quantifying functional selectivity and agonist bias. ACS Chem. Neurosci. 3, 193-203 (2012
63. Hill, A. The mode of action of nicotine and curari, determined by the form of the contraction curve and the method of temperature coefficients. J. Physiol. 39, 361-373 (1909
64. Pedregosa, F., et al. Scikit-learn: machine learning in Python. J. Mach. Learn. Res. 12, 2825-2830 (2011