1454
E. Edink et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1448–1454
4. Bencherif, M.; Lippiello, P. M.; Lucas, R.; Marrero, M. B. Cell. Mol. Life Sci. 2011,
68, 931.
conserved among the human nAChR subtypes, whereas the residue
(Ser165 in Ac-AChBP) that stabilizes the open lobeline pocket con-
formation is located in a highly variable region. As a consequence,
due to differential stabilization of rotameric states of the gate-
keeper tyrosine residue, there may exist pronounced differences
in the accessibility of the lobeline pocket between nAChR subtypes.
However, additional experiments using site-directed mutagenesis
and/or molecular probes are required to determine if the
lobeline-pocket can be targeted to obtain nAChR subtype-selectivity.
In summary, novel dibenzosuberyl- and benzoate substituted
tropines were designed using a structure-based fragment-merging
hit-optimization approach. Distinct SAR of the novel compound
series was observed between two AChBP species variants and
5. de Jonge, W. J.; Ulloa, L. Br. J. Pharmacol. 2007, 151, 915.
6. Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold, E. P.; Huang, J.;
Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C. B.; Shrikhande, A.; Heym, J. H.;
Schaeffer, E.; Rollema, H.; Lu, Y.; Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.;
Schulz, D. W.; Tingley, F. D., 3rd; O’Neill, B. T. J. Med. Chem. 2005, 48, 3474.
7. Potts, L. A.; Garwood, C. L. Am. J. Health Syst. Pharm. 2007, 64, 1381.
8. Brejc, K.; van Dijk, W. J.; Klaassen, R. V.; Schuurmans, M.; van Der Oost, J.; Smit,
A. B.; Sixma, T. K. Nature 2001, 411, 269.
9. 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. Nature 2001, 411, 261.
10. Celie, P. H.; Klaassen, R. V.; van Rossum-Fikkert, S. E.; van Elk, R.; van Nierop, P.;
Smit, A. B.; Sixma, T. K. J. Biol. Chem. 2005, 280, 26457.
11. Hansen, S. B.; Sulzenbacher, G.; Huxford, T.; Marchot, P.; Taylor, P.; Bourne, Y.
EMBO J. 2005, 24, 3635.
12. Celie, P. H.; van Rossum-Fikkert, S. E.; van Dijk, W. J.; Brejc, K.; Smit, A. B.;
Sixma, T. K. Neuron 2004, 41, 907.
between the a7 and a4b2 nAChR subtype. The AChBP species dif-
ferences were indicative of a difference in accessibility of a ligand-
inducible subpocket between AChBPs from different organisms.
Hereby, we have identified a region within the pocket that can
be scrutinized to unravel its importance for obtaining selectivity
amongst the fast number of nicotinic receptor subtypes. In addi-
tion, our studies are in line with previously published studies that
show that structure-based fragment merging can be an efficient
method for increasing binding affinity.32–34 The novel compounds
described in this study and the obtained structural understanding
can be used to focus on the subtle differences between the AChBPs
and nicotinic receptors, possibly the lobeline pocket accessibility,
and binding pose differences, that cause the observed selectivity
profiles and SAR differences.
13. Xiu, X.; Puskar, N. L.; Shanata, J. A.; Lester, H. A.; Dougherty, D. A. Nature 2009,
458, 534.
14. Edink, E.; Rucktooa, P.; Retra, K.; Akdemir, A.; Nahar, T.; Zuiderveld, O.; van Elk,
R.; Janssen, E.; van Nierop, P.; van Muijlwijk-Koezen, J.; Smit, A. B.; Sixma, T. K.;
Leurs, R.; de Esch, I. J. J. Am. Chem. Soc. 2011, 133, 5363.
15. Ulens, C.; Akdemir, A.; Jongejan, A.; van Elk, R.; Bertrand, S.; Perrakis, A.; Leurs,
R.; Smit, A. B.; Sixma, T. K.; Bertrand, D.; de Esch, I. J. J. Med. Chem. 2009, 52,
2372.
16. Whittaker, M.; Law, R. J.; Ichihara, O.; Hesterkamp, T.; Hallett, D. Drug Discov.
Today: Technol. 2010, 7, e163.
17. Lovell, S. C.; Word, J. M.; Richardson, J. S.; Richardson, D. C. Proteins 2000, 40,
389.
18. Experimental procedures can be found in the Supplementary data.
19. Pancrazio, J. J.; Kamatchi, G. L.; Roscoe, A. K.; Lynch, C., 3rd J. Pharmacol. Exp.
Ther. 1998, 284, 208.
20. van der Stelt, C.; Harms, A. F.; Nauta, W. T. J. Med. Pharm. Chem. 1961, 4, 335.
21. van der Stelt, C. F.; Funcke, A. B.; Tersteege, H. M.; Nauta, W. T. Arzneimittel
Forschung 1966, 16, 1342.
22. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
Org. Chem. 1996, 61, 3849.
Acknowledgments
23. Kovacs, E.; Schneider, J.; Ures, F. Izvestiya Akademii Nauk SSSR, Seriya
Khimicheskaya 1964, 320.
This work was supported by a grant of the Top Institute Pharma
D2-103 (to ABS), and received funding from the European Union
Seventh Framework Programme under grant agreement n°
HEALTH-F2-2007-202088 (‘‘NeuroCypres’’ project). AA was sup-
ported by a Mozaik research grant from the Netherlands Organiza-
tion for Scientific Research (NWO, project number 017.001.132).
We thank Eric Karssen for chemical synthesis of compound 31.
24. Maksay, G.; Nemes, P.; Biro, T. J. Med. Chem. 2004, 47, 6384.
25. Howarth, N. M.; Malpass, J. R.; Smith, C. R. Tetrahedron 1998, 54, 10899.
26. King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29, 3459.
27. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discov. Today 2004, 9, 430.
28. Verdonk, M. L.; Rees, D. C. ChemMedChem 2008, 3, 1179.
29. Edink, E.; Jansen, C.; Leurs, R.; de Esch, I. J. P. Drug Discov. Today: Technol. 2010,
7, e189.
30. Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061.
31. Dutertre, S.; Ulens, C.; Buttner, R.; Fish, A.; van Elk, R.; Kendel, Y.; Hopping, G.;
Alewood, P. F.; Schroeder, C.; Nicke, A.; Smit, A. B.; Sixma, T. K.; Lewis, R. J.
EMBO J. 2007, 26, 3858.
Supplementary data
32. Hughes, S. J.; Millan, D. S.; Kilty, I. C.; Lewthwaite, R. A.; Mathias, J. P.; O’Reilly,
M. A.; Pannifer, A.; Phelan, A.; Stuhmeier, F.; Baldock, D. A.; Brown, D. G. Bioorg.
Med. Chem. Lett. 2011, 21, 6586.
33. Madden, J.; Dod, J. R.; Godemann, R.; Kraemer, J.; Smith, M.; Biniszkiewicz, M.;
Hallett, D. J.; Barker, J.; Dyekjaer, J. D.; Hesterkamp, T. Bioorg. Med. Chem. Lett.
2010, 20, 5329.
Supplementary data associated with this article can be found, in
References and notes
34. Brough, P. A.; Barril, X.; Borgognoni, J.; Chene, P.; Davies, N. G.; Davis, B.;
Drysdale, M. J.; Dymock, B.; Eccles, S. A.; Garcia-Echeverria, C.; Fromont, C.;
Hayes, A.; Hubbard, R. E.; Jordan, A. M.; Jensen, M. R.; Massey, A.; Merrett, A.;
Padfield, A.; Parsons, R.; Radimerski, T.; Raynaud, F. I.; Robertson, A.; Roughley,
S. D.; Schoepfer, J.; Simmonite, H.; Sharp, S. Y.; Surgenor, A.; Valenti, M.; Walls,
S.; Webb, P.; Wood, M.; Workman, P.; Wright, L. J. Med. Chem. 2009, 52, 4794.
1. Gotti, C.; Clementi, F. Prog. Neurobiol. 2004, 74, 363.
2. Jensen, A. A.; Frolund, B.; Liljefors, T.; Krogsgaard-Larsen, P. J. Med. Chem. 2005,
48, 4705.
3. Kalamida, D.; Poulas, K.; Avramopoulou, V.; Fostieri, E.; Lagoumintzis, G.;
Lazaridis, K.; Sideri, A.; Zouridakis, M.; Tzartos, S. J. FEBS J. 2007, 274, 3799.