Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists

Journal of Medicinal Chemistry

Volumn 60, Issue 11, 2017, Pages 4693-4713

  Männel, Barbara ^a   Dengler, Daniela ^a   Shonberg, Jeremy ^a   Hübner, Harald ^a   Möller, Dorothee ^a   Gmeiner, Peter ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

5 [4 [4 (8 HYDROXYQUINOLIN 2(1H) ONE 5 YL) 1,4 DIAZEPAN 1 YL]BUTOXY]PYRAZOLO[1,5 A]PYRIDINE; 7 [4 [4 (5 HYDROXY 2H BENZO[B][1,4]OXAZIN 3(4H) ONE 8 YL) 1,4 DIAZEPAN 1 YL]BUTOXY] 3,4 DIHYDROQUINOLIN 2(1H) ONE; 8 CHLORO 2,3,4,5 TETRAHYDRO 3 METHYL 5 PHENYL 1H 3 BENZAZEPIN 7 OL HYDROGEN MALEATE; ALPHA ADRENERGIC RECEPTOR; ANTIPARKINSON AGENT; ARIPIPRAZOLE; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; BETA ARRESTIN 2; BI 167107; DOPAMINE; DOPAMINE 2 RECEPTOR; DOPAMINE 2 RECEPTOR STIMULATING AGENT; G PROTEIN COUPLED RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; LEVODOPA; LIGAND; N [2 [4 (2 METHOXYPHENYL) 1 PIPERAZINYL]ETHYL] N (2 PYRIDYL)CYCLOHEXANECARBOXAMIDE; PIPERAZINE DERIVATIVE; POTASSIUM CHANNEL HERG; PRAMIPEXOLE; PROCATEROL; QUINPIROLE; RADIOLIGAND; ROPINIROLE; ROTIGOTINE; SEROTONIN RECEPTOR; TRITIUM; UNC 0006; UNC 9975; UNC 9994; UNCLASSIFIED DRUG; BETA ARRESTIN; DOPAMINE RECEPTOR STIMULATING AGENT;

ANIMAL TISSUE; ARTICLE; AUTOMATED PATCH CLAMP; BINDING AFFINITY; CARBON NUCLEAR MAGNETIC RESONANCE; CARDIOTOXICITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOPAMINERGIC TRANSMISSION; DRUG DESIGN; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HEART ARRHYTHMIA; HYBRIDIZATION; HYDROGEN BOND; LIVER MICROSOME; MOLECULAR INTERACTION; NONHUMAN; PARKINSON DISEASE; PROTON NUCLEAR MAGNETIC RESONANCE; QT PROLONGATION; RAT; SCHIZOPHRENIA; ANIMAL; CHEMISTRY; CHO CELL LINE; CRICETULUS; DRUG EFFECTS; HUMAN; METABOLISM;

ANIMALS; BETA-ARRESTINS; CHO CELLS; CRICETULUS; DOPAMINE AGONISTS; HUMANS; PIPERAZINES; RECEPTORS, DOPAMINE D2;

EID: 85020463074     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.7b00363     Document Type: Article

References (68)

1. Beaulieu, J.-M.; Espinoza, S.; Gainetdinov, R. R. Dopamine Receptors-Iuphar Review 13 Br. J. Pharmacol. 2015, 172, 1-23 10.1111/bph.12906
2. Chaudhuri, K. R.; Schapira, A. H. V. Non-Motor Symptoms of Parkinson's Disease: Dopaminergic Pathophysiology and Treatment Lancet Neurol. 2009, 8, 464-474 10.1016/S1474-4422(09)70068-7
3. Oertel, W.; Schulz, J. B. Current and Experimental Treatments of Parkinson Disease: A Guide for Neuroscientists J. Neurochem. 2016, 139, 325-337 10.1111/jnc.13750
4. Cilia, R.; Akpalu, A.; Sarfo, F. S.; Cham, M.; Amboni, M.; Cereda, E.; Fabbri, M.; Adjei, P.; Akassi, J.; Bonetti, A.; Pezzoli, G. The Modern Pre-Levodopa Era of Parkinson's Disease: Insights into Motor Complications from Sub-Saharan Africa Brain 2014, 137, 2731-2742 10.1093/brain/awu195
5. Fahn, S.; Oakes, D.; Shoulson, I.; Kieburtz, K.; Rudolph, A.; Lang, A.; Olanow, C. W.; Tanner, C. Levodopa and the Progression of Parkinson's Disease N. Engl. J. Med. 2004, 351, 2498-2508 10.1056/NEJMoa033447
6. Jenner, P. Molecular Mechanisms of L-DOPA-Induced Dyskinesia Nat. Rev. Neurosci. 2008, 9, 665-677 10.1038/nrn2471
7. Bezard, E.; Brotchie, J. M.; Gross, C. E. Pathophysiology of Levodopa-Induced Dyskinesia: Potential for New Therapies Nat. Rev. Neurosci. 2001, 2, 577-588 10.1038/35086062
8. Reiter, E.; Ahn, S.; Shukla, A. K.; Lefkowitz, R. J. Molecular Mechanism of Beta-Arrestin-Biased Agonism at Seven-Transmembrane Receptors Annu. Rev. Pharmacol. Toxicol. 2012, 52, 179-197 10.1146/annurev.pharmtox.010909.105800
9. Peterson, S. M.; Pack, T. F.; Wilkins, A. D.; Urs, N. M.; Urban, D. J.; Bass, C. E.; Lichtarge, O.; Caron, M. G. Elucidation of G-Protein and B-Arrestin Functional Selectivity at the Dopamine D2 Receptor Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 7097-7102 10.1073/pnas.1502742112
10. Urban, J. D.; Clarke, W. P.; von Zastrow, M.; Nichols, D. E.; Kobilka, B.; Weinstein, H.; Javitch, J. A.; Roth, B. L.; Christopoulos, A.; Sexton, P. M.; Miller, K. J.; Spedding, M.; Mailman, R. B. Functional Selectivity and Classical Concepts of Quantitative Pharmacology J. Pharmacol. Exp. Ther. 2007, 320, 1-13 10.1124/jpet.106.104463
11. Neve, K. A. Functional Selectivity of G Protein-Coupled Receptor Ligands-New Opportunities for Drug Discovery. In The Receptors, 1st ed.; Neve, K. A., Ed.; Humana Press: Totowa, NJ; 2009; pp 25-40.
12. Urs, N. M.; Bido, S.; Peterson, S. M.; Daigle, T. L.; Bass, C. E.; Gainetdinov, R. R.; Bezard, E.; Caron, M. G. Targeting B-Arrestin2 in the Treatment of L-DOPA-Induced Dyskinesia in Parkinson's Disease Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E2517-E2526 10.1073/pnas.1502740112
13. Ahmed, M. R.; Berthet, A.; Bychkov, E.; Porras, G.; Li, Q.; Bioulac, B. H.; Carl, Y. T.; Bloch, B.; Kook, S.; Aubert, I.; Dovero, S.; Doudnikoff, E.; Gurevich, V. V.; Gurevich, E. V.; Bezard, E. Lentiviral Overexpression of GRK6 Alleviates L-DOPA-Induced Dyskinesia in Experimental Parkinson's Disease Sci. Transl. Med. 2010, 2, 28ra28 10.1126/scitranslmed.3000664
14. Allen, J. A.; Yost, J. M.; Setola, V.; Chen, X.; Sassano, M. F.; Chen, M.; Peterson, S.; Yadav, P. N.; Huang, X. P.; Feng, B.; Jensen, N. H.; Che, X.; Bai, X.; Frye, S. V.; Wetsel, W. C.; Caron, M. G.; Javitch, J. A.; Roth, B. L.; Jin, J. Discovery of Beta-Arrestin-Biased Dopamine D2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 18488-18493 10.1073/pnas.1104807108
15. Weichert, D.; Kruse, A. C.; Manglik, A.; Hiller, C.; Zhang, C.; Hübner, H.; Kobilka, B. K.; Gmeiner, P. Covalent Agonists for Studying G Protein-Coupled Receptor Activation Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 10744-10748 10.1073/pnas.1410415111
16. Ring, A. M.; Manglik, A.; Kruse, A. C.; Enos, M. D.; Weis, W. I.; Garcia, K. C.; Kobilka, B. K. Adrenaline-Activated Structure of Beta2-Adrenoceptor Stabilized by an Engineered Nanobody Nature 2013, 502, 575-579 10.1038/nature12572
17. Rasmussen, S. G. F.; Choi, H.-J.; Fung, J. J.; Pardon, E.; Casarosa, P.; Chae, P. S.; DeVree, B. T.; Rosenbaum, D. M.; Thian, F. S.; Kobilka, T. S.; Schnapp, A.; Konetzki, I.; Sunahara, R. K.; Gellman, S. H.; Pautsch, A.; Steyaert, J.; Weis, W. I.; Kobilka, B. K. Structure of a Nanobody-Stabilized Active State of the B2 Adrenoceptor Nature 2011, 469, 175-180 10.1038/nature09648
18. Warne, T.; Moukhametzianov, R.; Baker, J. G.; Nehme, R.; Edwards, P. C.; Leslie, A. G. W.; Schertler, G. F. X.; Tate, C. G. The Structural Basis for Agonist and Partial Agonist Action on a B1-Adrenergic Receptor Nature 2011, 469, 241-244 10.1038/nature09746
19. Weichert, D.; Stanek, M.; Hübner, H.; Gmeiner, P. Structure-Guided Development of Dual B2 Adrenergic/Dopamine D2 Receptor Agonists Bioorg. Med. Chem. 2016, 24, 2641-2653 10.1016/j.bmc.2016.04.028
20. Beattie, D.; Beer, D.; Bradley, M. E.; Bruce, I.; Charlton, S. J.; Cuenoud, B. M.; Fairhurst, R. A.; Farr, D.; Fozard, J. R.; Janus, D.; Rosethorne, E. M.; Sandham, D. A.; Sykes, D. A.; Trifilieff, A.; Turner, K. L.; Wissler, E. An Investigation into the Structure-Activity Relationships Associated with the Systematic Modification of the B2-Adrenoceptor Agonist Indacaterol Bioorg. Med. Chem. Lett. 2012, 22, 6280-6285 10.1016/j.bmcl.2012.07.096
21. Yoshizaki, S.; Tanimura, K.; Tamada, S.; Yabuuchi, Y.; Nakagawa, K. Sympathomimetic Amines Having a Carbostyril Nucleus J. Med. Chem. 1976, 19, 1138-1142 10.1021/jm00231a011
22. Yoshizaki, S.; Manabe, Y.; Tamada, S.; Nakagawa, K.; Tei, S. Isomers of Erythro-5-(1-Hydroxy-2-Isopropylaminobutyl)-8-Hydroxycarbostyril, a New Bronchodilator J. Med. Chem. 1977, 20, 1103-1104 10.1021/jm00218a024
23. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine, C.; Büttner, F. H.; Schnapp, A.; Konetzki, I. Discovery of Olodaterol, a Novel Inhaled B2-Adrenoceptor Agonist with a 24 H Bronchodilatory Efficacy Bioorg. Med. Chem. Lett. 2010, 20, 1410-1414 10.1016/j.bmcl.2009.12.087
24. Hoenke, C.; Bouyssou, T.; Tautermann, C. S.; Rudolf, K.; Schnapp, A.; Konetzki, I. Use of 5-Hydroxy-4H-Benzo[1,4]Oxazin-3-Ones as Beta2-Adrenoceptor Agonists Bioorg. Med. Chem. Lett. 2009, 19, 6640-6644 10.1016/j.bmcl.2009.10.013
25. Rosenbaum, D. M.; Zhang, C.; Lyons, J. A.; Holl, R.; Aragao, D.; Arlow, D. H.; Rasmussen, S. G.; Choi, H. J.; Devree, B. T.; Sunahara, R. K.; Chae, P. S.; Gellman, S. H.; Dror, R. O.; Shaw, D. E.; Weis, W. I.; Caffrey, M.; Gmeiner, P.; Kobilka, B. K. Structure and Function of an Irreversible Agonist-Beta(2) Adrenoceptor Complex Nature 2011, 469, 236-240 10.1038/nature09665
26. Chen, X.; McCorvy, J. D.; Fischer, M. G.; Butler, K. V.; Shen, Y.; Roth, B. L.; Jin, J. Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists J. Med. Chem. 2016, 59, 10601-10618 10.1021/acs.jmedchem.6b01208
27. Chen, X.; Sassano, M. F.; Zheng, L.; Setola, V.; Chen, M.; Bai, X.; Frye, S. V.; Wetsel, W. C.; Roth, B. L.; Jin, J. Structure-Functional Selectivity Relationship Studies of Beta-Arrestin-Biased Dopamine D(2) Receptor Agonists J. Med. Chem. 2012, 55, 7141-7153 10.1021/jm300603y
28. Möller, D.; Kling, R. C.; Skultety, M.; Leuner, K.; Hübner, H.; Gmeiner, P. Functionally Selective Dopamine D2, D3 Receptor Partial Agonists J. Med. Chem. 2014, 57, 4861-4875 10.1021/jm5004039
29. Möller, D.; Banerjee, A.; Uzuneser, T. C.; Skultety, M.; Huth, T.; Plouffe, B.; Hübner, H.; Alzheimer, C.; Friedland, K.; Müller, C. P.; Bouvier, M.; Gmeiner, P. Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]Pyridine Substructure J. Med. Chem. 2017, 60, 2908-2929 10.1021/acs.jmedchem.6b01857
30. Weichert, D.; Banerjee, A.; Hiller, C.; Kling, R. C.; Hübner, H.; Gmeiner, P. Molecular Determinants of Biased Agonism at the Dopamine D2 Receptor J. Med. Chem. 2015, 58, 2703-2717 10.1021/jm501889t
31. Pisani, L.; Catto, M.; Giangreco, I.; Leonetti, F.; Nicolotti, O.; Stefanachi, A.; Cellamare, S.; Carotti, A. Design, Synthesis, and Biological Evaluation of Coumarin Derivatives Tethered to an Edrophonium-Like Fragment as Highly Potent and Selective Dual Binding Site Acetylcholinesterase Inhibitors ChemMedChem 2010, 5, 1616-1630 10.1002/cmdc.201000210
32. Cerqueira, N. M. F. S. A.; Oliveira-Campos, A. M. F.; Coelho, P. J.; de Carvalho, L. H. M.; Samat, A.; Guglielmetti, R. Synthesis of Photochromic Dyes Based on Annulated Coumarin Systems Helv. Chim. Acta 2002, 85, 442-450 10.1002/1522-2675(200202)85:2<442::AID-HLCA442>3.0.CO;2-9
33. Mewshaw, R. E.; Zhou, D.; Zhou, P.; Shi, X.; Hornby, G.; Spangler, T.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree, T. H. Studies toward the Discovery of the Next Generation of Antidepressants. 3. Dual 5-HT1A and Serotonin Transporter Affinity within a Class of N-Aryloxyethylindolylalkylamines J. Med. Chem. 2004, 47, 3823-3842 10.1021/jm0304010
34. Chung, P.-Y.; Gambari, R.; Chen, Y.-X.; Cheng, C.-H.; Bian, Z.-X.; Chan, A. S.-C.; Tang, J. C.-O.; Leung, P. H.-M.; Chui, C.-H.; Lam, K.-H. Development of 8-Benzyloxy-Substituted Quinoline Ethers and Evaluation of Their Antimicrobial Activities Med. Chem. Res. 2015, 24, 1568-1577 10.1007/s00044-014-1217-4
35. Manninen, V. M.; Omar, W. A. E.; Heiskanen, J. P.; Lemmetyinen, H. J.; Hormi, O. E. O. Synthesis and Characterization of Tris-(5-Amino-8-Hydroxyquinoline)Aluminum Complexes and Their Use as Anode Buffer Layers in Inverted Organic Solar Cells J. Mater. Chem. 2012, 22, 22971-22982 10.1039/c2jm35292c
36. Oshiro, Y.; Sato, S.; Kurahashi, N.; Tanaka, T.; Kikuchi, T.; Tottori, K.; Uwahodo, Y.; Nishi, T. Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties: Synthesis and Pharmacology of 7-[4-(4-Phenyl-1-Piperazinyl)Butoxy]-3,4-Dihydro-2(1H)-Quinolinone Derivatives J. Med. Chem. 1998, 41, 658-667 10.1021/jm940608g
37. Gmeiner, P.; Huebner, H.; Skultety, M. Preparation of Indolizines and Aza-Analog Derivatives Thereof as CNS Active Compounds. WO2008113559A2, 2008.
38. Kühhorn, J.; Götz, A.; Hübner, H.; Thompson, D.; Whistler, J.; Gmeiner, P. Development of a Bivalent Dopamine D(2) Receptor Agonist J. Med. Chem. 2011, 54, 7911-7919 10.1021/jm2009919
39. Tabor, A.; Weisenburger, S.; Banerjee, A.; Purkayastha, N.; Kaindl, J. M.; Hübner, H.; Wei, L.; Grömer, T. W.; Kornhuber, J.; Tschammer, N.; Birdsall, N. J. M.; Mashanov, G. I.; Sandoghdar, V.; Gmeiner, P. Visualization and Ligand-Induced Modulation of Dopamine Receptor Dimerization at the Single Molecule Level Sci. Rep. 2016, 6, 33233 10.1038/srep33233
40. Ohno, Y. Therapeutic Role of 5-HT1A Receptors in the Treatment of Schizophrenia and Parkinson's Disease CNS Neurosci. Ther. 2011, 17, 58-65 10.1111/j.1755-5949.2010.00211.x
41. Lohse, M. J.; Benovic, J. L.; Codina, J.; Caron, M. G.; Lefkowitz, R. J. Beta-Arrestin: A Protein That Regulates Beta-Adrenergic Receptor Function Science 1990, 248, 1547-1550 10.1126/science.2163110
42. Lefkowitz, R. J.; Shenoy, S. K. Transduction of Receptor Signals by Beta-Arrestins Science 2005, 308, 512-517 10.1126/science.1109237
43. Urs, N. M.; Snyder, J. C.; Jacobsen, J. P. R.; Peterson, S. M.; Caron, M. G. Deletion of Gsk3β in D2r-Expressing Neurons Reveals Distinct Roles for B-Arrestin Signaling in Antipsychotic and Lithium Action Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 20732-20737 10.1073/pnas.1215489109
44. Lane, J. R.; Powney, B.; Wise, A.; Rees, S.; Milligan, G. G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors J. Pharmacol. Exp. Ther. 2008, 325, 319-330 10.1124/jpet.107.134296
45. Strange, P. G. Use of the Gtpγs Binding Assay for Analysis of Ligand Potency and Efficacy at G Protein-Coupled Receptors Br. J. Pharmacol. 2010, 161, 1238-1249 10.1111/j.1476-5381.2010.00963.x
46. Gazi, L.; Nickolls, S.; Strange, P. G. Functional Coupling of the Human Dopamine D2 Receptor with Galphai1, Galphai2, Galphai3, and Galphao G Proteins: Evidence for Agonist Regulation of G Protein Selectivity Br. J. Pharmacol. 2003, 138, 775-786 10.1038/sj.bjp.0705116
47. Jiang, M.; Spicher, K.; Boulay, G.; Wang, Y.; Birnbaumer, L. Most Central Nervous System D2 Dopamine Receptors Are Coupled to Their Effectors by Go Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 3577-3582 10.1073/pnas.051632598
48. Lohse, M. J.; Hoffmann, C. Arrestin Interactions with G Protein-Coupled Receptors Handb. Exp. Pharmacol. 2014, 219, 15-56 10.1007/978-3-642-41199-1-2
49. Urs, N. M.; Gee, S. M.; Pack, T. F.; McCorvy, J. D.; Evron, T.; Snyder, J. C.; Yang, X.; Rodriguiz, R. M.; Borrelli, E.; Wetsel, W. C.; Jin, J.; Roth, B. L.; O'Donnell, P.; Caron, M. G. Distinct Cortical and Striatal Actions of a B-Arrestin-Biased Dopamine D2 Receptor Ligand Reveal Unique Antipsychotic-Like Properties Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E8178-E8186 10.1073/pnas.1614347113
50. Peterson, S. M.; Pack, T. F.; Caron, M. G. Receptor, Ligand and Transducer Contributions to Dopamine D2 Receptor Functional Selectivity PLoS One 2015, 10, e0141637 10.1371/journal.pone.0141637
51. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings Adv. Drug Delivery Rev. 2001, 46, 3-26 10.1016/S0169-409X(00)00129-0
52. Prachayasittikul, V.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. 8-Hydroxyquinolines: A Review of Their Metal Chelating Properties and Medicinal Applications Drug Des., Dev. Ther. 2013, 7, 1157-1178 10.2147/DDDT.S49763
53. Swart, P. J.; Oelen, W. E. M.; Bruins, A. P.; Tepper, P. G.; de Zeeuw, R. A. Determination of the Dopamine D2 Agonist N-0923 and Its Major Metabolites in Perfused Rat Livers by HPLC-UV-Atmospheric Pressure Ionization Mass Spectrometry J. Anal. Toxicol. 1994, 18, 71-77 10.1093/jat/18.2.71
54. Obach, R. S. Prediction of Human Clearance of Twenty-Nine Drugs from Hepatic Microsomal Intrinsic Clearance Data: An Examination of in Vitro Half-Life Approach and Nonspecific Binding to Microsomes Drug Metab. Dispos. 1999, 27, 1350-1359
55. Peters, S. A. Appendix I. In Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry, 1st ed.; John Wiley & Sons: Hoboken, NJ, 2012; pp 407-421.
56. Recanatini, M.; Poluzzi, E.; Masetti, M.; Cavalli, A.; De Ponti, F. Qt Prolongation through hERG K+ Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development Med. Res. Rev. 2005, 25, 133-166 10.1002/med.20019
57. Raschi, E.; Ceccarini, L.; De Ponti, F.; Recanatini, M. Herg-Related Drug Toxicity and Models for Predicting hERG Liability and QT Prolongation Expert Opin. Drug Metab. Toxicol. 2009, 5, 1005-1021 10.1517/17425250903055070
58. Sanguinetti, M. C.; Mitcheson, J. S. Predicting Drug-hERG Channel Interactions That Cause Acquired Long QT Syndrome Trends Pharmacol. Sci. 2005, 26, 119-124 10.1016/j.tips.2005.01.003
59. Poluzzi, E.; Raschi, E.; Moretti, U.; De Ponti, F. Drug-Induced Torsades De Pointes: Data Mining of the Public Version of the FDA Adverse Event Reporting System (AERS) Pharmacoepidemiol. Drug Saf. 2009, 18, 512-518 10.1002/pds.1746
60. Löber, S.; Hübner, H.; Tschammer, N.; Gmeiner, P. Recent Advances in the Search for D3- and D4-Selective Drugs: Probes, Models and Candidates Trends Pharmacol. Sci. 2011, 32, 148-157 10.1016/j.tips.2010.12.003
61. Hiller, C.; Kling, R. C.; Heinemann, F. W.; Meyer, K.; Hübner, H.; Gmeiner, P. Functionally Selective Dopamine D2/D3 Receptor Agonists Comprising an Enyne Moiety J. Med. Chem. 2013, 56, 5130-5141 10.1021/jm400520c
62. Tschammer, N.; Elsner, J.; Goetz, A.; Ehrlich, K.; Schuster, S.; Ruberg, M.; Kühhorn, J.; Thompson, D.; Whistler, J.; Hübner, H.; Gmeiner, P. Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D3 Receptor Binding, Functional Selectivity, and Analysis of Receptor-Ligand Interactions J. Med. Chem. 2011, 54, 2477-2491 10.1021/jm101639t
63. Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.; Randall, R. J. Protein Measurement with the Folin Phenol Reagent J. Biol. Chem. 1951, 193, 265-275
64. Hübner, H.; Haubmann, C.; Utz, W.; Gmeiner, P. Conjugated Enynes as Nonaromatic Catechol Bioisosteres: Synthesis, Binding Experiments and Computational Studies of Novel Dopamine Receptor Agonists Recognizing Preferentially the D3 Subtype J. Med. Chem. 2000, 43, 756-762 10.1021/jm991098z
65. Black, J. W.; Leff, P. Operational Models of Pharmacological Agonism Proc. R. Soc. London, Ser. B 1983, 220, 141-162 10.1098/rspb.1983.0093
66. Namkung, Y.; Radresa, O.; Armando, S.; Devost, D.; Beautrait, A.; Le Gouill, C.; Laporte, S. A. Quantifying Biased Signaling in GPCRs Using BRET-Based Biosensors Methods 2016, 92, 5-10 10.1016/j.ymeth.2015.04.010
67. 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. 2014, 85, 492-509 10.1124/mol.113.088880
68. Manglik, A.; Lin, H.; Aryal, D. K.; McCorvy, J. D.; Dengler, D.; Corder, G.; Levit, A.; Kling, R. C.; Bernat, V.; Hübner, H.; Huang, X.-P.; Sassano, M. F.; Giguère, P. M.; Löber, S.; Duan, D.; Scherrer, G.; Kobilka, B. K.; Gmeiner, P.; Roth, B. L.; Shoichet, B. K. Structure-Based Discovery of Opioid Analgesics with Reduced Side Effects Nature 2016, 537, 185-190 10.1038/nature19112