Dragoni, S.; Valoti, M.; Colombo, G.; Castelli, M. P.; Gessa, G.
L.; Corelli, F. J. Med. Chem. 2013, 56, 3620−3635.
1. Chen, L.-H.; Sun, B.; Zhang, Y.; Xu, T.-J.; Xia, Z.-X.; Liu, J.-F.;
Nan, F.-J. ACS Med. Chem. Lett. 2014, 5, 742−747.
ball-and-stick. H-bonds and aromatic π–π stacking are shown as black and
cyan dashed lines, respectively.
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The difluoromethyl ketones represent the newest class of
agonists of the GABAB receptor, and further investigations
through synthesis, biological evaluation, and computational
analysis have not only revealed that enhancements in potency are
possible but also that the structure–activity relationships are
distinct from other classes of agonists that display the structure of
GABA. The critical nature of the substituent on the aromatic
group of the -hydroxy difluoromethyl ketone was characterized.
Also, the identification of the -amino difluoromethyl ketones as
potent agonists of the GABAB receptor is another significant
advance.
2. Geng, Y.; Bush, M.; Mosyak, L.; Wang, F.; Fan, Q. R. Nature
2
013, 504, 254–259.
3. Brown, K. M.; Roy, K. K.; Hockerman, G. H.; Doerksen, R. J.;
Colby, D. A. J. Med. Chem. 2015, 58, 6336–6347.
14. Dambrova, M.; Zvejniece, L.; Liepinsh, E.; Cirule, H.; Zharkova,
O.; Veinberg, G.; Kalvinsh, I. Eur. J. Pharmacol. 2008, 583,
1
28−134.
1
5. Pirard, B.; Carrupt, P.-A.; Testa, B.; Tsai, R.-S.; Berthelot, P.;
Vaccher, C.; Debaert, M.; Durant, F. Bioorg. Med. Chem. 1995, 3,
1
537−1545.
16. Xu, F.; Peng, G.; Phan, T.; Dilip, U.; Chen, J. L.; Chernov-Rogan,
T.; Zhang, X.; Grindstaff, K.; Annamalai, T.; Koller, K.; Gallop,
M. A.; Wustrow, D. J. Bioorg. Med. Chem. Lett. 2011, 21, 6582–
6
585.
Acknowledgments
1
7. Hinton, T.; Chebib, M.; Johnston, G. A. R. Bioorg. Med. Chem.
Lett. 2008, 18, 402−404.
The authors acknowledge funding from the University of
Mississippi, the Ralph W. and Grace M. Showalter Research
Trust, and the National Institute of General Medical Sciences
18. Ong, J.; Bexis, S.; Marino, V.; Parker, D. A. S.; Kerr, D. I. B.;
Froestl, W. Eur. J. Pharmacol. 2001, 412, 27−37.
1
9. Han, C.; Salyer, A. E.; Kim, E. H.; Jiang, X.; Jarrard R. E.;
Powers, M. S.; Kirchhoff, A. M.; Salvador, T. K.; Chester, J. A.;
Hockerman, G. H.; Colby, D. A. J. Med. Chem. 2013, 56, 2456–
(Grant P20GM104932). Its contents are solely the responsibility
of the authors and do not necessarily represent the official view
of the National Institutes of Health (NIH). Receptor binding
profiles was generously provided by the National Institute of
Mental Health's Psychoactive Drug Screening Program, Contract
2
465.
20. Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133,
5802–5805.
2
2
1. Han C.; Kim, E. H.; Colby, D. A. Synlett 2012, 23, 1559–1563
2. Xie, C.; Wu, L.; Mei, H.; Soloshonok, V. A.; Han, J.; Pan, Y.
Tetrahedron Lett. 2014, 55, 5908–5910.
#
HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is
Directed by Bryan L. Roth, MD, PhD at the University of North
Carolina at Chapel Hill and Project Officer Jamie Driscoll at
NIMH, Bethesda MD, USA.
2
3. Xie, C.; Wu, L.; Zhou, J.; Mei, H.; Soloshonok, V. A.; Han, J.;
Pan, Y. J. Fluorine Chem. 2015, 172, 13–21.
24. See Supplementary Material for details.
2
5. Nguyen, A. L.; Khatri, H. R.; Woods, J. R.; Baldwin, C. S.;
Fronczek, F. R.; Colby, D. A. J. Org. Chem. 2018, 83, 3109–3118.
6. Besnard, J.; Ruda, G. F.; Setola, V.; Abecassis, K.; Rodriguiz, R.
M.; Huang, X. P.; Norval, S.; Sassano, M. F.; Shin, A. I.; Webster,
L. A.; Simeons, F. R.; Stojanovski, L.; Prat, A.; Seidah, N. G.;
Constam, D. B.; Bickerton, G. R.; Read, K. D.; Wetsel, W. C.;
Gilbert, I. H.; Roth, B. L.; Hopkins, A. L. Nature 2012, 492, 212–
220.
References and notes
2
1
2
.
.
Froestl, W. Future Med. Chem. 2011, 3, 163–175.
Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. J.
Med. Chem. 2008, 51, 7243–7252.
3
4
.
.
Froestl, W. Adv. Pharmacol. 2010, 58, 19–62.
Mizukami, K.; Sasaki, M.; Ishikawa, M.; Iwakiri, M.; Hidaka, S.;
Shiraishi, H.; Iritani, S. Neurosci. Lett. 2000, 283, 101−104.
Balerio, G. N.; Rubio, M. C. Pharmacol. Res. 2002, 46, 281−286.
ꢀlstermarꢁ, ꢂ.ꢃ ꢀmin, ꢄ.ꢃ ꢅinn, S. ꢆ.ꢃ ꢇlebrinꢈ, ꢉ.ꢃ ꢊꢋellstrꢌm,
O.; Fitzpatrick, K.; Geiss, W. B.; Gottfries, J.; Guzzo, P. R.;
Harding, J. ꢍ.ꢃ ꢎolmꢏn, A.; Kothare, M.; Lehmann, A.; Mattsson,
J. P.; Nilsson, ꢄ.ꢃ Sꢐndꢏn, G.; Swanson, M.; von Unge, S.; Woo,
A. M.; Wyle, M. J.; Zheng, X. J. Med. Chem. 2008, 51,
27. ꢊꢑꢒ, C.; Hardegger, L. A.; Baitsch, L.; Schweizer, W. B.; Meyer,
S.; Bur, D.; Diederich, F. Org. Biomol. Chem. 2009, 7,
3947−3957.
28. Moore, C. L.; Leatherwood, D. D.; Diehl, T. S.; Selkoe, D. J.;
Wolfe, M. S. J. Med. Chem. 2000, 43, 3434−3442.
5
6
.
.
Supplementary Material
4
315−4320.
7
8
.
.
.
Froestl, W.; Mickel, S. J.; Hall, R. G.; von Sprecher, G.; Strub, D.;
Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J. J. Med.
Chem. 1995, 38, 3297–3312.
Froestl, W.; Mickel, S. J.; von Sprecher, G.; Diel, P. J.; Hall, R.
G.; Maier, L.; Strub, D.; Melillo, V.; Baumann, P. A. J. Med.
Chem. 1995, 38, 3313–3331.
Experimental procedures; molecular modeling procedures and
1
19
13
supporting results; and H,
F, and
C NMR spectra.
Supplementary data associated with this article can be found in
the online version.
9
1
Guery, S.; Floersheim, P.; Kaupmann, K.; Froestl, W. Bioorg.
Med. Chem. Lett. 2007, 17, 6206−6211.
0. Mugnaini, C.; Pedani, V.; Casu, A.; Lobina, C.; Casti, A.;
Maccioni, P.; Porcu, A.; Giunta, D.; Lamponi, S.; Solinas, M.;