Synthesis, pharmacology, and biostructural characterization of novel α4β2 nicotinic acetylcholine receptor agonists

Journal of Medicinal Chemistry

Volumn 56, Issue 3, 2013, Pages 940-951

  Ussing, Christine A ^a   Hansen, Camilla P ^a,e   Petersen, Jette G ^a   Jensen, Anders A ^a   Rohde, Line A H ^a,b   Ahring, Philip K ^c   Nielsen, Elsebet Ø ^c   Kastrup, Jette S ^a   Gajhede, Michael ^a   Frølund, Bente ^a   Balle, Thomas ^a,d  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b NEUROSEARCH A S   (Denmark)

^c Aniona ApS   (Denmark)

^d UNIVERSITY OF SYDNEY   (Australia)

^e National Institute for Health Data and Disease Control   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

3 (DIMETHYLAMINO)BUTYL DIMETHYLCARBAMATE; 4 BROMO N,N DIMETHYLBUTAN 2 AMMONIUM BROMIDE; [3 (PYRAZIN 2 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (1 METHYL 1H IMIDAZOL 2 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (1,4 DIMETHYL 1H IMIDAZOL 2 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (1H PYRAZOL 1 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (4 BROMO 1 METHYL 1H IMIDAZOL 2 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (4,5 DIBROMO 1 METHYL 1H IMIDAZOL 2 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (PYRIDIN 3 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; [4 (THIAZOL 2 YLOXY)BUT 2 YL] N,N DIMETHYLAMMONIUM OXALATE; HETEROCYCLIC COMPOUND; NICOTINIC AGENT; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; BINDING SITE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; LYMNAEA STAGNALIS; NONHUMAN; OOCYTE; VOLTAGE CLAMP; XENOPUS LAEVIS;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; LYMNAEA; MEMBRANE POTENTIALS; MODELS, MOLECULAR; NICOTINIC ANTAGONISTS; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; RADIOLIGAND ASSAY; RECEPTORS, NICOTINIC; XENOPUS LAEVIS;

EID: 84873913747     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301409f     Document Type: Article

References (43)

1. Zoli, M.; Léna, C.; Picciotto, M. R.; Changeux, J. P. Identification of four classes of brain nicotinic receptors using beta2 mutant mice J. Neurosci. 1998, 18, 4461-4472
2. Paterson, D.; Nordberg, A. Neuronal nicotinic receptors in the human brain Prog. Neurobiol. 2000, 61, 75-111
3. Maloku, E.; Kadriu, B.; Zhubi, A.; Dong, E.; Pibiri, F.; Satta, R.; Guidotti, A. Selective alpha4beta2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons Neuropsychopharmacology 2011, 36, 1366-1374
4. Mineur, Y. S.; Einstein, E. B.; Seymour, P. A.; Coe, J. W.; O'Neill, B, T.; Rollema, H.; Picciotto, M. R. alpha4beta2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties Behav. Pharmacol. 2011, 22, 291-299
5. Hays, J. T.; Ebbert, J. O.; Sood, A. Efficacy and safety of varenicline for smoking cessation Am. J. Med. 2008, 121, S32-42
6. Rollema, H.; Chambers, L. K.; Coe, J. W.; Glowa, J.; Hurst, R. S.; Lebel, L. A.; Lu, Y.; Mansbach, R. S.; Mather, R. J.; Rovetti, C. C.; Sands, S. B.; Schaeffer, E.; Schulz, D. W.; Tingley, F. D., 3rd; Williams, K. E. Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid Neuropharmacology 2007, 52, 985-994
7. West, R.; Zatonski, W.; Cedzynska, M.; Lewandowska, D.; Pazik, J.; Aveyard, P.; Stapleton, J. Placebo-controlled trial of cytisine for smoking cessation N. Engl. J. Med. 2011, 365, 1193-1200
8. Dowell, C.; Olivera, B. M.; Garrett, J. E.; Staheli, S. T.; Watkins, M.; Kuryatov, A.; Yoshikami, D.; Lindstrom, J. M.; McIntosh, J. M. Alpha-conotoxin PIA is selective for alpha6 subunit-containing nicotinic acetylcholine receptors J. Neurosci. 2003, 23, 8445-8452
9. Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-Larsen, P. Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations J. Med. Chem. 2005, 48, 4705-4745
10. Yamauchi, J. G.; Gomez, K.; Grimster, N.; Dufouil, M.; Nemecz, A.; Fotsing, J. R.; Ho, K. Y.; Talley, T. T.; Sharpless, K. B.; Fokin, V. V.; Taylor, P. Synthesis of selective agonists for the alpha7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates Mol. Pharmacol. 2012, 82, 687-699
11. Moroni, M.; Zwart, R.; Sher, E.; Cassels, B. K.; Bermudez, I. alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine Mol. Pharmacol. 2006, 70, 755-768
12. Nelson, M. E.; Kuryatov, A.; Choi, C. H.; Zhou, Y.; Lindstrom, J. Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors Mol. Pharmacol. 2003, 63, 332-341
13. Harpsøe, K.; Ahring, P. K.; Christensen, J. K.; Jensen, M. L.; Peters, D.; Balle, T. Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors J. Neurosci. 2011, 31, 10759-10766
14. Timmermann, D. B.; Sandager-Nielsen, K.; Dyhring, T.; Smith, M.; Jacobsen, A. M.; Nielsen, E. Ø.; Grunnet, M.; Christensen, J. K.; Peters, D.; Kohlhaas, K.; Olsen, G. M.; Ahring, P. K. Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors Br. J. Pharmacol. 2012, 167, 164-182
15. Brejc, K.; van Dijk, W. J.; Klaassen, R. V.; Schuurmans, M.; van Der Oost, J.; Smit, A. B.; Sixma, T. K. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors Nature 2001, 411, 269-276
16. Celie, P. H.; van Rossum-Fikkert, S. E.; van Dijk, W. J.; Brejc, K.; Smit, A. B.; Sixma, T. K. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures Neuron 2004, 41, 907-914
17. Hansen, S. B.; Sulzenbacher, G.; Huxford, T.; Marchot, P.; Taylor, P.; Bourne, Y. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations EMBO J. 2005, 24, 3635-3646
18. Rohde, L. A.; Ahring, P. K.; Jensen, M. L.; Nielsen, E. Ø.; Peters, D.; Helgstrand, C.; Krintel, C.; Harpsøe, K.; Gajhede, M.; Kastrup, J. S.; Balle, T. Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: unique role of halogen bonding revealed J. Biol. Chem. 2012, 287, 4248-4259
19. Smit, A. B.; Syed, N. I.; Schaap, D.; van Minnen, J.; Klumperman, J.; Kits, K. S.; Lodder, H.; van der Schors, R. C.; van Elk, R.; Sorgedrager, B.; Brejc, K.; Sixma, T. K.; Geraerts, W. P. A glia-derived acetylcholine-binding protein that modulates synaptic transmission Nature 2001, 411, 261-268
20. Hibbs, R. E.; Sulzenbacher, G.; Shi, J.; Talley, T. T.; Conrod, S.; Kem, W. R.; Taylor, P.; Marchot, P.; Bourne, Y. Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor EMBO J. 2009, 28, 3040-3051
21. Brams, M.; Gay, E. A.; Sáez, J. C.; Guskov, A.; van Elk, R.; van der Schors, R. C.; Peigneur, S.; Tytgat, J.; Strelkov, S. V.; Smit, A. B.; Yakel, J. L.; Ulens, C. Crystal structures of a cysteine-modified mutant in loop D of acetylcholine-binding protein J. Biol. Chem. 2011, 286, 4420-4428
22. Hansen, C. P.; Jensen, A. A.; Balle, T.; Bitsch-Jensen, K.; Hassan, M. M.; Liljefors, T.; Frølund, B. Carbamoylcholine analogs as nicotinic acetylcholine receptor agonists-structural modifications of 3-(dimethylamino) butyl dimethylcarbamate (DMABC) Bioorg. Med. Chem. Lett. 2009, 19, 87-91
23. Hansen, C. P.; Jensen, A. A.; Christensen, J. K.; Balle, T.; Liljefors, T.; Frølund, B. Novel acetylcholine and carbamoylcholine analogues: development of a functionally selective alpha4beta2 nicotinic acetylcholine receptor agonist J. Med. Chem. 2008, 51, 7380-7395
24. Jensen, A. A.; Mikkelsen, I.; Frølund, B.; Bräuner-Osborne, H.; Falch, E.; Krogsgaard-Larsen, P. Carbamoylcholine homologs: novel and potent agonists at neuronal nicotinic acetylcholine receptors Mol. Pharmacol. 2003, 64, 865-875
25. Jensen, A. A.; Mikkelsen, I.; Frølund, B.; Frydenvang, K.; Brehm, L.; Jaroszewski, J. W.; Bräuner-Osborne, H.; Falch, E.; Krogsgaard-Larsen, P. Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors Eur. J. Pharmacol. 2004, 497, 125-137
26. Søkilde, B.; Mikkelsen, I.; Stensbøl, T. B.; Andersen, B.; Ebdrup, S.; Krogsgaard-Larsen, P.; Falch, E. Analogues of carbacholine: synthesis and relationship between structure and affinity for muscarinic and nicotinic acetylcholine receptors Arch. Pharm. (Weinheim, Ger.) 1996, 329, 95-104
27. Gotti, C.; Zoli, M.; Clementi, F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance Trends Pharmacol. Sci. 2006, 27, 482-491
28. Doyle, F. P.; Mehta, M. D.; Ward, R.; Bainbrid., J.; Brown, D. M. Chemistry and pharmacology of some esters derived from basic alcohols J. Med. Chem. 1965, 8, 571-576
29. Eisele, J. L.; Bertrand, S.; Galzi, J. L.; Devillers-Thiery, A.; Changeux, J. P.; Bertrand, D. Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities Nature 1993, 366, 479-483
30. Bissantz, C.; Kuhn, B.; Stahl, M. A medicinal chemist's guide to molecular interactions J. Med. Chem. 2010, 53, 5061-5084
31. Parker, M. J.; Harvey, S. C.; Luetje, C. W. Determinants of agonist binding affinity on neuronal nicotinic receptor beta subunits J. Pharmacol. Exp. Ther. 2001, 299, 385-391
32. Billen, B.; Spurny, R.; Brams, M.; van Elk, R.; Valera-Kummer, S.; Yakel, J. L.; Voets, T.; Bertrand, D.; Smit, A. B.; Ulens, C. Molecular actions of smoking cessation drugs at alpha4beta2 nicotinic receptors defined in crystal structures of a homologous binding protein Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 9173-9178
33. Shahsavar, A.; Kastrup, J. S.; Nielsen, E. Ø.; Kristensen, J. L.; Gajhede, M.; Balle, T. Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHbetaE suggests a unique mode of antagonism PLoS One 2012, 7, e40757
34. Mirza, N. R.; Larsen, J. S.; Mathiasen, C.; Jacobsen, T. A.; Munro, G.; Erichsen, H. K.; Nielsen, A. N.; Troelsen, K. B.; Nielsen, E. O.; Ahring, P. K. NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2- carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy J. Pharmacol. Exp. Ther. 2008, 327, 954-968
35. Xiao, Y.; Meyer, E. L.; Thompson, J. M.; Surin, A.; Wroblewski, J.; Kellar, K. J. Rat α3/β4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function Mol. Pharmacol. 1998, 54, 322-333
36. Winn, M. D.; Ballard, C. C.; Cowtan, K. D.; Dodson, E. J.; Emsley, P.; Evans, P. R.; Keegan, R. M.; Krissinel, E. B.; Leslie, A. G.; McCoy, A.; McNicholas, S. J.; Murshudov, G. N.; Pannu, N. S.; Potterton, E. A.; Powell, H. R.; Read, R. J.; Vagin, A.; Wilson, K. S. Overview of the CCP4 suite and current developments Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 235-242
37. Kabsch, W. XDS Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 125-132
38. McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser crystallographic software J. Appl. Crystallogr. 2007, 40, 658-674
39. Adams, P. D.; Afonine, P. V.; Bunkóczi, G.; Chen, V. B.; Davis, I. W.; Echols, N.; Headd, J. J.; Hung, L. W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: a comprehensive Python-based system for macromolecular structure solution Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 213-221
40. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501
41. Moriarty, N. W.; Grosse-Kunstleve, R. W.; Adams, P. D. Electronic ligand builder and optimization workbench (eLBOW): a tool for ligand coordinate and restraint generation Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 1074-1080
42. Chen, V. B.; Arendall, W. B., 3rd; Headd, J. J.; Keedy, D. A.; Immormino, R. M.; Kapral, G. J.; Murray, L. W.; Richardson, J. S.; Richardson, D. C. MolProbity: all-atom structure validation for macromolecular crystallography Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 12-21
43. Laskowski, R. A.; Macarthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK-a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291