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Table 3. Binding affinity of compounds 2, 46, 51, and 54 for human b-
ARs and selectivity versus b1- and b2-ARs
References and notes
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Science 1989, 245, 1118–1121.
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A.; Chiu, S. H.; Deng, L.; Forrest, M. J.; Hegarty-
Friscino, B.; Guan, X. M.; Hom, G. J.; Hutchins, J. E.;
Kelly, L. J.; Mathvink, R. J.; Metzger, J. M.; Miller, R.
R.; Ok, H. O.; Parmee, E. R.; Saperstein, R.; Strader, C.
D.; Stearns, R. A.; Thompson, G. M.; Tota, L.; Vicario, P.
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8. All compounds were characterized by 1H NMR, mass
spectrometry, and HPLC analysis before submission for
biological evaluation.
OH
H
N
H
N
S
S
O O
Me
N
H
R
Compd
R
Binding Ki (nM)a
Selectivityb
Versus Versus
b1 b2
3.6 1.7
3.2
b3
b1
b2
2
H
OMe
30
14
110
43
51
25
46
51
54
1.9
9.5
OCH2CO2H 17
OSO2Me 4.0
480 160 29
66 48 17
12
a Binding affinity is reported as Ki, the binding inhibition constant,
determined by inhibition of 125I-iodocyanopindolol binding.
b Binding selectivity is defined as the ratio of b3 (Ki) to b1 (Ki) or b2
(Ki).
decreased the agonistic activity for the b2-AR
(EC50 = 60nM).
The selected compounds 2, 46, 51, and 54 were then sub-
jected to binding assays for the human b1À3-ARs. As
shown in Table 3, the methanesulfonate 54 exhibited a
high affinity for the b3-AR with a binding constant
(Ki) of 4.0nM. Binding selectivity of 54 for the b3-AR
over the b1- and b2-ARs was 17- and 12-fold, respec-
tively. Although the Ki value of 51 for the b3-AR
(Ki = 17nM) was lower than that of 54, 51 showed excel-
lent selectivity over the b1-AR (29-fold). The methoxy
derivative 46 also showed moderate affinity for the b3-
AR (Ki = 14nM), but the selectivity over the b1- and
b2-ARs was low (<4-fold). It is interesting to note that
the binding affinity of the methanesulfonate 54 is supe-
rior to those of the carboxylic acid derivative 51 and
the methoxy derivative 50. In addition, 54 has excellent
subtype selectivity comparable to 47. These data indi-
cate that the sulfonate moiety contributes not only to
potency but also to selectivity over the b1- and b2-ARs.
9. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012. A review.
10. The enantiomeric excess of the secondary alcohol was up
to 95% after recrystallization from hexane/i-Pr2O.
11. Fujii, A.; Fujima, Y.; Harada, H.; Ikunaka, M.; Inoue, T.;
Kato, S.; Matsuyama, K. Tetrahedron: Asymmetry 2001,
12, 3235–3240.
12. Repk, D. B.; Ferguson, W. J. J. Heterocycl. Chem. 1976,
13, 775–778.
13. The CHO cells expressing either human b1-, b2-, or b3-
ARs were prepared as described in Kato, S.; Harada, H.;
Taoka, I.; Kawashima, H. PCT Patent Application, WO
2000044721, 2000 and Kato, S.; Harada, H.; Hirokawa,
Y.; Yoshida, N.; Kawashima, H. PCT Patent Application,
WO 9616938, 1996.
14. For example: (a) Parmee, E. R.; Brockunier, L. L.; He, J.;
Singh, S. B.; Candelore, M. R.; Cascieri, M. A.; Deng, L.;
Liu, Y.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber,
A. E. Bioorg. Med. Chem. Lett. 2000, 10, 2283–2286; (b)
Mathvink, R. J.; Tolman, J. S.; Chitty, D.; Candelore, M.
R.; Cascieri, M. A.; Colwell, L. F., Jr.; Deng, L.; Feeney,
W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.;
Miller, R. R.; Stearns, R. A.; Tota, L.; Wyvratt, M. J.;
Fisher, M. H.; Weber, A. E. J. Med. Chem. 2000, 43,
3832–3836; (c) Weber, A. E.; Mathvink, R. J.; Perkins, L.;
Hutchins, J. E.; Candelore, M. R.; Tota, L.; Strader, C.
D.; Wyvratt, M. J.; Fisher, M. H. Bioorg. Med. Chem.
Lett. 1998, 8, 1101–1106.
In summary, we synthesized the tryptamine-based aryl-
sulfonamide derivatives with various alkyloxy or sulfo-
nate groups at the 7-position of the indole ring, and
evaluated their agonistic activity for the b1À3-ARs. We
found that the methanesulfonate 54 was a highly potent
b3-AR agonist (EC50 = 0.21nM, IA = 97%) with excel-
lent subtype selectivity over the b1- and b2-ARs (210-
and 86-fold, respectively). In a binding assay, 54 exhib-
ited a strong affinity for the b3-AR (Ki = 4.0nM), and
good selectivity over the b1- and b2-ARs (17- and 12-
fold, respectively). Further studies on 54 and related
compounds will be reported in due course.
15. Sum, F. W.; Wong, V.; Han, S.; Largis, E.; Mulvey, R.;
Tillett, J. Bioorg. Med. Chem. Lett. 2003, 13, 2191–
2194.