4062
S. D. Banister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4059–4063
Table 1
r
subtypes, warranting the further investigation of cubane for the
Binding affinities and r2 subtype selectivities of N-substituted 7-azabicy-
clo[2.2.1]heptanes and pyrrolidines for
design of potent, but subtype non-selective,
r receptor ligands.
r receptors
The 7-azabicyclo[2.2.1]heptane scaffold represents a promising
candidate for the development of selective 2 ligands, particularly
when substituted with electron-rich benzylic systems, as in 14. In
order to further improve 2 receptor affinity and selectivity, future
work will focus on the exploration of alkoxy substitution patterns
(as well as alternative electron-donating substituents) around the
Compound
Ki (nM SEM)a
r2 Selectivity
r
r1
r2
r
12
13
14
15
16
17
22
23
24
25
32
33
34
35
36
41
42
43
44
NA
NA
NA
NA
22
7.0 0.3
276 47
103
399 21
251 38
43.1 7.2
6352 342
>25
>39
>232
>1.6
1.2
0.39
2.1
3.5
benzyl ring of 14. The development of potent and highly
r2-selec-
1
18
18
1
1
tive 7-azanorbornanes will enable the delineated investigation of
the role of the r2 receptor in CNS disorders such as anxiety,
depression, and substance abuse.
131
5
8
29.5 5.1
517 103
11.9 2.3
852 35
1611 47
661 27
NA
410 30
658 25
246 32
3516 165
3826 364
7.4
10
120
NA
NA
NA
NA
51
NA
NA
NA
NA
9
Acknowledgments
>11
>6.2
>15
—
0.12
>15
>40
>2.8
>260
Ki determinations for targets included in Table 1 and in the SI
were generously provided by the National Institute of Mental
Health’s Psychoactive Drug Screening Program, Contract
#NO1MH32004 (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 Driscol at NIMH, Bethesda MD, USA. For
experimental details please refer to the PDSP web site http://
5
39
1
a
Ki values represent the mean SEM of four experiments. NA = less than 50%
inhibition of specific binding at 10 M.
l
Supplementary data
Phenethylpyrrolidine (41) showed a five-fold reduction in r2
affinity (Ki = 658 nM) when compared to corresponding 7-azabicy-
Supplementary data associated with this article can be
clo[2.2.1]heptane, however, the reduction in
more pronounced (Ki >10 M). The same trend was observed for
3-fluorophenethyl-substituted pyrrolidine (42), which showed
approximately eight times lower affinity for 2 (Ki = 246 nM) than
the analogous 7-azanorbornane, but negligible affinity for r1 (Ki
>10 M). Compound 44, N-(3-(3-fluorophenyl)propyl)pyrrolidine,
showed a marked improvement in r2 binding (Ki = 39 nM), but
was still devoid of r1 affinity (Ki >10 M), resulting in an anoma-
lously selective r2 ligand (r1 2 = 256) for the series.
Replacement of the phenyl ring of 32 with a 3-pyridine ring (35)
abolished affinity for either receptor subtype (Ki > 10 M in each
case), and homologation to 2-pyridylethyl-substituted pyrrolidine
(43) did little to improve binding. Although the pyridine-con-
taining 15 and 24 were the least active azanorbornanes, the
binding of pyridine-derived pyrrolidines 35 and 43 was even
r1 affinity was much
l
References
r
1. Banister, S.; Kassiou, M. Curr. Pharm. Des. 2012, 18, 884.
2. Quirion, R.; Bowen, W. D.; Itzhak, Y.; Junien, J. L.; Musacchio, J. M.; Rothman, R.
B.; Su, T. P.; Tam, S. W.; Taylor, D. P. Trends Pharmacol. Sci. 1992, 13, 85.
3. Guitart, X.; Codony, X.; Monroy, X. Psychopharmacology (Berl.) 2004, 174, 301.
4. Kekuda, R.; Prasad, P. D.; Fei, Y. J.; Leibach, F. H.; Ganapathy, V. Biochem.
Biophys. Res. Commun. 1996, 229, 553.
5. Hayashi, T.; Su, T.-P. Cell 2007, 131, 596.
6. Tsai, S.-Y.; Hayashi, T.; Mori, T.; Su, T.-P. Cent. Nerv. Syst. Agents Med. Chem.
2009, 9, 184.
7. Hayashi, T.; Su, T. P. J. Pharmacol. Exp. Ther. 2003, 306, 726.
8. Hayashi, T.; Maurice, T.; Su, T. P. J. Pharmacol. Exp. Ther. 2000, 293, 788.
9. Aydar, E.; Palmer, C. P.; Klyachko, V. A.; Jackson, M. B. Neuron 2002, 34, 399.
10. Hellewell, S. B.; Bruce, A.; Feinstein, G.; Orringer, J.; Williams, W.; Bowen, W. D.
Eur. J. Pharmacol. 1994, 268, 9.
11. Zeng, C.; Vangveravong, S.; Xu, J.; Chang, K. C.; Hotchkiss, R. S.; Wheeler, K. T.;
Shen, D.; Zhuang, Z. P.; Kung, H. F.; Mach, R. H. Cancer Res. 2007, 67, 6708.
12. Xu, J.; Zeng, C.; Chu, W.; Pan, F.; Rothfuss, J. M.; Zhang, F.; Tu, Z.; Zhou, D.; Zeng,
D.; Vangveravong, S.; Johnston, F.; Spitzer, D.; Chang, K. C.; Hotchkiss, R. S.;
Hawkins, W. G.; Wheeler, K. T.; Mach, R. H. Nat. Commun. 2011, 2, 380.
13. Fishback, J. A.; Robson, M. J.; Xu, Y.-T.; Matsumoto, R. R. Pharmacol. Ther. 2010,
127, 271.
l
l
/r
r
l
r
r
poorer, consistent with the observed trend for reduced
when moving the pyrrolidine unit.
r affinities
Several structure–affinity relationships can be identified from
the binding data presented in Table 1. In the context of previ-
ously reported binding profiles of trishomocubanes of type 3,
steric reduction of the polycyclic framework was detrimental to
binding at both subtypes. Removal of a single ethylene bridge
r
r
14. Tam, S. W.; Cook, L. Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 5618.
15. Bowen, W. D.; Moses, E. L.; Tolentino, P. J.; Walker, J. M. Eur. J. Pharmacol. 1990,
177, 111.
r
from the 7-azanorbornane analogs, to give the corresponding pyr-
rolidines, significantly attenuated r2 binding. Within the 7-azabi-
cyclo[2.2.1]heptane series, benzylic substituents conferred the
greatest r2 selectivities, while increasing the distance between
the aryl group and the nitrogen atom increased affinity for both
r1 and r2 (particularly the former), resulting in r2 ligands with
low levels of subtype discrimination.
16. Itzhak, Y.; Kassim, C. O. Eur. J. Pharmacol. 1990, 176, 107.
17. Narita, N.; Hashimoto, K.; Tomitaka, S.; Minabe, Y. Eur. J. Pharmacol. 1996, 307,
117.
18. Nguyen, E. C.; McCracken, K. A.; Liu, Y.; Pouw, B.; Matsumoto, R. R.
Neuropharmacology 2005, 49, 638.
19. Maurice, T.; Martin-Fardon, R.; Romieu, P.; Matsumoto, R. R. Neurosci. Biobehav.
Rev. 2002, 26, 499.
20. Matsumoto, R. R.; Liu, Y.; Lerner, M.; Howard, E. W.; Brackett, D. J. Eur. J.
Pharmacol. 2003, 469, 1.
The high r1 affinity of cyclohexyl-derived azanorbornane 16,
containing an aliphatic rather than aromatic group, indicates that
21. Matsumoto, R. R. Expert Rev. Clin. Pharmacol. 2009, 2, 351.
22. Glennon, R. A. Mini Rev. Med. Chem. 2005, 5, 927.
23. Glennon, R. A. Rev. Bras. Cienc. Farm. 2005, 41, 1.
24. Liu, X.; Banister, S. D.; Christie, M. J.; Banati, R.; Meikle, S.; Coster, M. J.; Kassiou,
M. Eur. J. Pharmacol. 2007, 555, 37.
25. Moussa, I. A.; Banister, S. D.; Beinat, C.; Giboureau, N.; Reynolds, A. J.; Kassiou,
M. J. Med. Chem. 2010, 53, 6228.
26. Moussa, I. A.; Banister, S. D.; Akladios, F. N.; Chua, S. W.; Kassiou, M. Bioorg.
Med. Chem. Lett. 2011, 21, 5707.
27. Moussa, I. A.; Banister, S. D.; Giboureau, N.; Meikle, S. R.; Kassiou, M. Bioorg.
Med. Chem. Lett. 2011, 21, 6820.
electronic factors are more important for
r1 than r2 binding. This
is further supported by the anomalous r1 affinity of the cyclo-
hexyl-bearing 36 within the pyrrolidine series. However, the possi-
bility of multiple binding orientations for non-aromatic
cannot be excluded and may contribute to the observed binding
profiles. Aliphatic compound 17, the first receptor ligand com-
prising a cubane subunit, showed remarkably high affinity for both
r ligands
r