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Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor

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Medicinal Chemistry, and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia
*J.R.L.: phone, +61 3 9903 9095; e-mail, [email protected]
*B.C.: phone, +61 3 9903 9556; e-mail, [email protected]
Cite this: J. Med. Chem. 2015, 58, 13, 5287–5307
Publication Date (Web):June 8, 2015
https://doi.org/10.1021/acs.jmedchem.5b00581
Copyright © 2015 American Chemical Society

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    Abstract

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    We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.

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    Derivation of allosteric ternary complex model from an operational model of agonism; a csv file containing molecular formula strings. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b00581.

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    30. Christopher J. Draper-Joyce, Ravi Kumar Verma, Mayako Michino, Jeremy Shonberg, Anitha Kopinathan, Carmen Klein Herenbrink, Peter J. Scammells, Ben Capuano, Ara M. Abramyan, David M. Thal, Jonathan A. Javitch, Arthur Christopoulos, Lei Shi, J. Robert Lane. The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Scientific Reports 2018, 8 (1) https://doi.org/10.1038/s41598-018-19642-1
    31. . Tetrahydroisoquinolines. 2018, 356-413. https://doi.org/10.1002/9781118686263.ch10
    32. Christopher J. Draper-Joyce, Mayako Michino, Ravi Kumar Verma, Carmen Klein Herenbrink, Jeremy Shonberg, Anitha Kopinathan, Peter J. Scammells, Ben Capuano, David M. Thal, Jonathan A. Javitch, Arthur Christopoulos, Lei Shi, J. Robert Lane. The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D 2 receptor. Biochemical Pharmacology 2018, 148 , 315-328. https://doi.org/10.1016/j.bcp.2018.01.002
    33. Ravi Kumar Verma, Ara M. Abramyan, Mayako Michino, R. Benjamin Free, David R. Sibley, Jonathan A. Javitch, J. Robert Lane, Lei Shi, . The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors. PLOS Computational Biology 2018, 14 (1) , e1005948. https://doi.org/10.1371/journal.pcbi.1005948
    34. Irene Fasciani, Ilaria Pietrantoni, Mario Rossi, Clotilde Mannoury la Cour, Gabriella Aloisi, Francesco Marampon, Marco Scarselli, Mark J. Millan, Roberto Maggio. Distinctive binding properties of the negative allosteric modulator, [ 3 H]SB269,652, at recombinant dopamine D 3 receptors. European Journal of Pharmacology 2018, 819 , 181-189. https://doi.org/10.1016/j.ejphar.2017.12.002
    35. Barbara Männel, Harald Hübner, Dorothée Möller, Peter Gmeiner. β-Arrestin biased dopamine D2 receptor partial agonists: Synthesis and pharmacological evaluation. Bioorganic & Medicinal Chemistry 2017, 25 (20) , 5613-5628. https://doi.org/10.1016/j.bmc.2017.08.037
    36. Mario Rossi, Irene Fasciani, Francesco Marampon, Roberto Maggio, Marco Scarselli. The First Negative Allosteric Modulator for Dopamine D 2 and D 3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs. Molecular Pharmacology 2017, 91 (6) , 586-594. https://doi.org/10.1124/mol.116.107607
    37. A.M. Jones. Privileged Structures and Motifs (Synthetic and Natural Scaffolds). 2017, 116-152. https://doi.org/10.1016/B978-0-12-409547-2.12316-9
    38. Antoni Cortés, Estefanía Moreno, Mar Rodríguez-Ruiz, Enric I. Canela, Vicent Casadó. Targeting the dopamine D3 receptor: an overview of drug design strategies. Expert Opinion on Drug Discovery 2016, 11 (7) , 641-664. https://doi.org/10.1080/17460441.2016.1185413
    39. Anitha Kopinathan, Peter J Scammells, J Robert Lane, Ben Capuano. Multivalent approaches and beyond: novel tools for the investigation of dopamine D 2 receptor pharmacology. Future Medicinal Chemistry 2016, 8 (11) , 1349-1372. https://doi.org/10.4155/fmc-2016-0010

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