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B. Wenzel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2163–2166
aminobenzovesamicol.21 (iii) At last, the sterically demanding 4-
fluorobenzoyl group might reduce the binding affinity because it
is placed within the molecule at a region which is obviously sensi-
tive for steric bulk. This was also observed for prezamicol deriva-
tives19 with substituents bound on the nitrogen of the
cyclohexanol ring in opposite to the piperidinyl moiety. As we have
recently shown in a QSAR study,22 this region is not favorable for
steric interactions. More promising would be an incorporation of
the 4-fluorobenzoyl group on the pyrrole nitrogen (in opposite to
the OH-group of the cyclohexanol ring) of regioisomer ( )-6a. This
region is favorable for bulky substituents as shown for FBT
(Ki = 0.44 0.11 nM),23 FBMV (Ki = 27.5 8.8 nM)9 or the amino-
benzovesamicol derivative NEFA (Ki = 0.32 0.04 nM).24 However,
as described in this Letter, the N-substitution of the pyrrole ring
was not stable during the nucleophilic epoxide ring opening reac-
tion. Therefore, further synthetic work and structural modifications
within this new class of pyrrolovesamicols are needed to verify
their suitability as VAChT ligands and to get detailed information
on structure-activity relationship.
3. Kilbourn, M. R.; Hockley, B.; Lee, L.; Sherman, P.; Quesada, C.; Frey, K. A.;
Koeppe, R. A. Nucl. Med. Biol. 2009, 36, 489.
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Anderluh, M.; Brust, P.; Guilloteau, D.; Emond, P. Bioorg. Med. Chem. 2010, 18,
7659.
5. Jung, Y. W.; Frey, K. A.; Mulholland, G. K.; del Rosario, R.; Sherman, P. S.; Raffel,
D. M.; Van Dort, M. E.; Kuhl, D. E.; Gildersleeve, D. L.; Wieland, D. M. J. Med.
Chem. 1996, 39, 3331.
6. Mulholland, G. K.; Wieland, D. M.; Kilbourn, M. R.; Frey, K. A.; Sherman, P. S.;
Carey, J. E.; Kuhl, D. E. Synapse 1998, 30, 263.
7. Efange, S. M.; Mach, R. H.; Khare, A.; Michelson, R. H.; Nowak, P. A.; Evora, P. H.
Appl. Radiat. Isot. 1994, 45, 465.
8. Efange, S. M.; Michelson, R. H.; Khare, A. B.; Thomas, J. R. J. Med. Chem. 1993, 36,
1754.
9. Sorger, D.; Scheunemann, M.; Vercouillie, J.; Grossmann, U.; Fischer, S.; Hiller,
A.; Wenzel, B.; Roghani, A.; Schliebs, R.; Steinbach, J.; Brust, P.; Sabri, O. Nucl.
Med. Biol. 2009, 36, 17.
10. Sorger, D.; Scheunemann, M.; Grossmann, U.; Fischer, S.; Vercouille, J.; Hiller,
A.; Wenzel, B.; Roghani, A.; Schliebs, R.; Brust, P.; Sabri, O.; Steinbach, J. Nucl.
Med. Biol. 2008, 35, 185.
11. Wenzel, B.; Hiller, A.; Fischer, S.; Sorger, D.; Deuther-Conrad, W.;
Scheunemann, M.; Brust, P.; Sabri, O.; Steinbach, J. J. Labelled Compd.
Radiopharm. 2011, 54, 426.
12. Wenzel, B.; Fischer, S.; Brust, P.; Steinbach, J. J. Chromatogr., A 2010, 1217, 7884.
13. Details in Supplementary data.
14. Remers, W. A.; Gibs, G. J.; Pidacks, C.; Weiss, M. J. J. Org. Chem. 1971, 36, 279.
15. Saracoglu, N.; Cavdar, H. Tetrahedron 2005, 61, 2401.
16. Scopes, D. I. C.; Allen, M. S.; Hignett, G. J.; Wilson, N. D. V.; Harris, M.; Joule, J. A.
J. Chem. Soc., Perkin Trans. 1 1977, 2376.
Acknowledgments
17. Wang, R.; Hong, L.; Liu, C. X.; Sun, W. S.; Wang, L.; Wong, K. Org. Lett. 2009, 11,
2177.
The authors thank Achim Hiller for providing LRMS data and
Lothar Hennig (Universität Leipzig) for measurement of NMR spec-
tra. VAChT cells were used by courtesy of Ali Roghani. The project
was financially supported by the Deutsche Forschungsgemeinschaft
(WE 2927/1-2).
18. Crystallographic data (excluding structure factors) for the structures have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 853323 for ( )-6a and CCDC 853324 for ( )-6b. Copies of
the data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, fax: +44 1223 336033 or e-mail:
19. Efange, S. M.; Khare, A.; Parsons, S. M.; Bau, R.; Metzenthin, T. J. Med. Chem.
1993, 36, 985.
Supplementary data
20. Efange, S. M.; Khare, A. B.; Mach, R. H.; Parsons, S. M. J. Med. Chem. 1999, 42,
2862.
21. Rogers, G. A.; Parsons, S. M.; Anderson, D. C.; Nilsson, L. M.; Bahr, B. A.;
Kornreich, W. D.; Kaufman, R.; Jacobs, R. S.; Kirtman, B. J. Med. Chem. 1989, 32,
1217.
Supplementary data (detailed descriptions of syntheses and the
binding assay as well as analytical data (NMR, HRMS, HPLC) and
crystal structure data) associated with this article can be found,
22. Szymoszek, A.; Wenzel, B.; Scheunemann, M.; Steinbach, J.; Schüürmann, G. J.
Med. Chem. 2008, 51, 2128.
23. Efange, S. M.; Mach, R. H.; Smith, C. R.; Khare, A. B.; Foulon, C.; Akella, S. K.;
Childers, S. R.; Parsons, S. M. Biochem. Pharmacol. 1995, 49, 791.
24. Rogers, G. A.; Kornreich, W. D.; Hand, K.; Parsons, S. M. Mol. Pharmacol. 1993,
44, 633.
References and notes
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