Structure-based development of a subtype-selective orexin 1 receptor antagonist

Hellmann, Jan; Drabek, Matthäus; Yin, Jie; Gunera, Jakub; Pröll, Theresa; Kraus, Frank; Langmead, Christopher J.; Hübner, Harald; Weikert, Dorothee; Kolb, Peter; Rosenbaum, Daniel M.; Gmeiner, Peter

doi:10.1073/pnas.2002704117

Structure-based development of a subtype-selective orexin 1 receptor antagonist

Journal Article · Tue Jul 28 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2002704117· OSTI ID:1671133

^[1]; ^[2]; Yin, Jie ^[3]; Gunera, Jakub ^[2]; Pröll, Theresa ^[1]; ^[1]; Langmead, Christopher J. ^[4]; ^[1]; ^[1]; ^[2]; ^[2]; ^[1]

Friedrich-Alexander-Univ. Erlangen-Nürnberg (Germany)
Philipps Univ., Marburg (Germany)
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Monash Univ., Melbourne, VIC (Australia)

Orexin receptors belong to the superfamily of G-protein–coupled receptors (GPCRs) which represent the largest class of drug targets in humans. Despite the recent progress in structural biology, the development of subtype-selective orexin receptor and GPCR ligands in general remains challenging, due to the high sequence similarity among individual receptor subtypes. However, subtype-selective molecules are key to discerning the individual contributions of receptor subtypes to (patho-)physiology. Starting from the clinically used, non–subtype-selective orexin receptor antagonist suvorexant, we demonstrate how docking, crystallography, medicinal chemistry, and in vitro pharmacology can be combined to exploit single amino acid sequence differences for the discovery of subtype-selective probes. Such compounds will help to better understand orexin receptor pharmacology and develop promising drug candidates.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

OSTI ID:: 1671133

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 30 Vol. 117; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (46)

Discovery and Characterization of ACT-335827, an Orally Available, Brain Penetrant Orexin Receptor Type 1 Selective Antagonist Steiner, Michel A.; Gatfield, John; Brisbare-Roch, Catherine ChemMedChem, Vol. 8, Issue 6 https://doi.org/10.1002/cmdc.201300003	journal	April 2013
Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach Heidmann, Bibia; Gatfield, John; Roch, Catherine ChemMedChem, Vol. 11, Issue 19 https://doi.org/10.1002/cmdc.201600175	journal	July 2016
Differential expression of orexin receptors 1 and 2 in the rat brain Marcus, Jacob N.; Aschkenasi, Carl J.; Lee, Charlotte E. The Journal of Comparative Neurology, Vol. 435, Issue 1 https://doi.org/10.1002/cne.1190	journal	January 2001
FRED and HYBRID docking performance on standardized datasets McGann, Mark Journal of Computer-Aided Molecular Design, Vol. 26, Issue 8 https://doi.org/10.1007/s10822-012-9584-8	journal	June 2012
Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs McGaughey, Georgia; Bayly, Christopher I.; Cox, Christopher D. Journal of Computer-Aided Molecular Design, Vol. 28, Issue 1 https://doi.org/10.1007/s10822-014-9710-x	journal	January 2014
Lemborexant: First Approval Scott, Lesley J. Drugs, Vol. 80, Issue 4 https://doi.org/10.1007/s40265-020-01276-1	journal	February 2020
Distribution of orexin receptor mRNA in the rat brain Trivedi, Prashant; Yu, Hong; MacNeil, Douglas J. FEBS Letters, Vol. 438, Issue 1-2 https://doi.org/10.1016/S0014-5793(98)01266-6	journal	October 1998
Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior Sakurai, Takeshi; Amemiya, Akira; Ishii, Makoto Cell, Vol. 92, Issue 4 https://doi.org/10.1016/S0092-8674(00)80949-6	journal	February 1998
The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene Lin, Ling; Faraco, Juliette; Li, Robin Cell, Vol. 98, Issue 3 https://doi.org/10.1016/S0092-8674(00)81965-0	journal	August 1999
Reduced Number of Hypocretin Neurons in Human Narcolepsy Thannickal, Thomas C.; Moore, Robert Y.; Nienhuis, Robert Neuron, Vol. 27, Issue 3 https://doi.org/10.1016/S0896-6273(00)00058-1	journal	September 2000
d-myo-Inositol 1-phosphate as a surrogate of d-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation Trinquet, Eric; Fink, Michel; Bazin, Hervé Analytical Biochemistry, Vol. 358, Issue 1 https://doi.org/10.1016/j.ab.2006.08.002	journal	November 2006
A review of the role of orexin system in pain modulation Razavi, Bibi Marjan; Hosseinzadeh, Hossein Biomedicine & Pharmacotherapy, Vol. 90 https://doi.org/10.1016/j.biopha.2017.03.053	journal	June 2017
F13. Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of the Selective Orexin-1 Receptor Antagonist JNJ-61393215: Results From the First-In-Human and Multiple Ascending Dose Studies Salvadore, Giacomo; Brooks, Sander; Cathy, Bleys Biological Psychiatry, Vol. 85, Issue 10 https://doi.org/10.1016/j.biopsych.2019.03.550	journal	May 2019
The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor Perrey, David A.; Decker, Ann M.; Li, Jun-Xu Bioorganic & Medicinal Chemistry, Vol. 23, Issue 17 https://doi.org/10.1016/j.bmc.2015.07.013	journal	September 2015
Selective orexin receptor antagonists Lebold, Terry P.; Bonaventure, Pascal; Shireman, Brock T. Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 17 https://doi.org/10.1016/j.bmcl.2013.06.057	journal	September 2013
Multiplexing of Multicolor Bioluminescence Resonance Energy Transfer Breton, Billy; Sauvageau, Étienne; Zhou, Joris Biophysical Journal, Vol. 99, Issue 12 https://doi.org/10.1016/j.bpj.2010.10.025	journal	December 2010
Therapeutics development for addiction: Orexin-1 receptor antagonists Perrey, David A.; Zhang, Yanan Brain Research, Vol. 1731 https://doi.org/10.1016/j.brainres.2018.08.025	journal	March 2020
Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs Lee, Sang-Min; Booe, Jason M.; Pioszak, Augen A. European Journal of Pharmacology, Vol. 763 https://doi.org/10.1016/j.ejphar.2015.05.013	journal	September 2015
Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats Zhou, Luyi; Smith, Rachel J.; Do, Phong H. Neuropharmacology, Vol. 63, Issue 7 https://doi.org/10.1016/j.neuropharm.2012.07.044	journal	December 2012
Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia Roecker, Anthony J.; Cox, Christopher D.; Coleman, Paul J. Journal of Medicinal Chemistry, Vol. 59, Issue 2 https://doi.org/10.1021/acs.jmedchem.5b00832	journal	September 2015
Binding-Site Compatible Fragment Growing Applied to the Design of β ₂ -Adrenergic Receptor Ligands Chevillard, Florent; Rimmer, Helena; Betti, Cecilia Journal of Medicinal Chemistry, Vol. 61, Issue 3 https://doi.org/10.1021/acs.jmedchem.7b01558	journal	January 2018
Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis Rappas, Mathieu; Ali, Ammar A. E.; Bennett, Kirstie A. Journal of Medicinal Chemistry, Vol. 63, Issue 4 https://doi.org/10.1021/acs.jmedchem.9b01787	journal	December 2019
Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database Hawkins, Paul C. D.; Skillman, A. Geoffrey; Warren, Gregory L. Journal of Chemical Information and Modeling, Vol. 50, Issue 4 https://doi.org/10.1021/ci100031x	journal	March 2010
FRED Pose Prediction and Virtual Screening Accuracy McGann, Mark Journal of Chemical Information and Modeling, Vol. 51, Issue 3 https://doi.org/10.1021/ci100436p	journal	February 2011
Role of orexin receptors in obesity: from cellular to behavioral evidence Perez-Leighton, C. E.; Butterick-Peterson, T. A.; Billington, C. J. International Journal of Obesity, Vol. 37, Issue 2 https://doi.org/10.1038/ijo.2012.30	journal	March 2012
A role for lateral hypothalamic orexin neurons in reward seeking Harris, Glenda C.; Wimmer, Mathieu; Aston-Jones, Gary Nature, Vol. 437, Issue 7058 https://doi.org/10.1038/nature04071	journal	August 2005
Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant Yin, Jie; Mobarec, Juan Carlos; Kolb, Peter Nature, Vol. 519, Issue 7542 https://doi.org/10.1038/nature14035	journal	December 2014
Structure-based discovery of opioid analgesics with reduced side effects Manglik, Aashish; Lin, Henry; Aryal, Dipendra K. Nature, Vol. 537, Issue 7619 https://doi.org/10.1038/nature19112	journal	August 2016
Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET Namkung, Yoon; Le Gouill, Christian; Lukashova, Viktoria Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms12178	journal	July 2016
Crystallizing membrane proteins using lipidic mesophases Caffrey, Martin; Cherezov, Vadim Nature Protocols, Vol. 4, Issue 5 https://doi.org/10.1038/nprot.2009.31	journal	April 2009
Trends in GPCR drug discovery: new agents, targets and indications Hauser, Alexander S.; Attwood, Misty M.; Rask-Andersen, Mathias Nature Reviews Drug Discovery, Vol. 16, Issue 12 https://doi.org/10.1038/nrd.2017.178	journal	October 2017
The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness Sakurai, Takeshi Nature Reviews Neuroscience, Vol. 8, Issue 3 https://doi.org/10.1038/nrn2092	journal	February 2007
Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors Yin, Jie; Babaoglu, Kerim; Brautigam, Chad A. Nature Structural & Molecular Biology, Vol. 23, Issue 4 https://doi.org/10.1038/nsmb.3183	journal	March 2016
Probing the activation-promoted structural rearrangements in preassembled receptor–G protein complexes Galés, Céline; Van Durm, Joost J. J.; Schaak, Stéphane Nature Structural & Molecular Biology, Vol. 13, Issue 9 https://doi.org/10.1038/nsmb1134	journal	August 2006
Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists Williams, Jodi T.; Gatfield, John; Roch, Catherine MedChemComm, Vol. 6, Issue 6 https://doi.org/10.1039/C5MD00074B	journal	January 2015
Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists Liu, Hongtao; Hofmann, Josefa; Fish, Inbar Proceedings of the National Academy of Sciences, Vol. 115, Issue 47 https://doi.org/10.1073/pnas.1813988115	journal	November 2018
The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity de Lecea, L.; Kilduff, T. S.; Peyron, C. Proceedings of the National Academy of Sciences, Vol. 95, Issue 1 https://doi.org/10.1073/pnas.95.1.322	journal	January 1998
Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands: Binding kinetics contrast functional antagonism Mould, R.; Brown, J.; Marshall, F. H. British Journal of Pharmacology, Vol. 171, Issue 2 https://doi.org/10.1111/bph.12245	journal	December 2013
Orexin/hypocretin receptor signalling cascades: Orexin receptor signalling cascades Kukkonen, J. P.; Leonard, C. S. British Journal of Pharmacology, Vol. 171, Issue 2 https://doi.org/10.1111/bph.12324	journal	December 2013
Determining the Potency and Molecular Mechanism of Action of Insurmountable Antagonists Kenakin, Terry; Jenkinson, Stephen; Watson, Christian Journal of Pharmacology and Experimental Therapeutics, Vol. 319, Issue 2 https://doi.org/10.1124/jpet.106.107375	journal	July 2006
In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist Beuckmann, Carsten Theodor; Suzuki, Michiyuki; Ueno, Takashi Journal of Pharmacology and Experimental Therapeutics, Vol. 362, Issue 2 https://doi.org/10.1124/jpet.117.241422	journal	May 2017
The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468 Treiber, Alexander; de Kanter, Ruben; Roch, Catherine Journal of Pharmacology and Experimental Therapeutics, Vol. 362, Issue 3 https://doi.org/10.1124/jpet.117.241596	journal	June 2017
Label-Free Kinetics: Exploiting Functional Hemi-Equilibrium to Derive Rate Constants for Muscarinic Receptor Antagonists Riddy, Darren M.; Valant, Celine; Rueda, Patricia Molecular Pharmacology, Vol. 88, Issue 4 https://doi.org/10.1124/mol.115.100545	journal	August 2015
D ₄ dopamine receptor high-resolution structures enable the discovery of selective agonists Wang, Sheng; Wacker, Daniel; Levit, Anat Science, Vol. 358, Issue 6361 https://doi.org/10.1126/science.aan5468	journal	October 2017
Current Phase II investigational therapies for insomnia Zisapel, Nava Expert Opinion on Investigational Drugs, Vol. 24, Issue 3 https://doi.org/10.1517/13543784.2015.987340	journal	October 2014
The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases Wang, Chunmei; Wang, Qinqin; Ji, Bingyuan Frontiers in Molecular Neuroscience, Vol. 11 https://doi.org/10.3389/fnmol.2018.00220	journal	June 2018

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