R. Kolanos et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5832–5835
5835
8. Glennon, R. A.; Lee, M.; Rangisetty, J. B.; Dukat, M.;
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itself. Nevertheless, 4 represents a rotamer that was not
calculated to be of low energy. This is probably a more
reasonable explanation for the observed low affinity
of 4.
Overall then, the results of this investigation (on com-
pounds with Ki values spanning a >10,000-fold range)
support the prior suggestion that N1-unsubstituted and
N1-benzenesulfonyl-substituted tryptamines are proba-
bly binding in a dissimilar fashion upon interaction with
5-HT6 receptors. It is, perhaps, a quirk of human nature
(and not an unreasonable one)16 to intuit that agents
sharing a common structural scaffold will likely bind
in a common fashion. This does not appear to be the
case, however, with the compounds examined in the
present investigation. Future SAR and QSAR studies,
particularly with the types of compounds described here,
should take this into account, and consider also that
agonists and antagonists, despite structural similarity,
need not bind in a similar manner. In addition, the high-
er affinity of 3 relative to 4—structurally constrained
rotational extremes of the benzenesulfonyl group of
6b—suggests that 3, more so than 4, represents a favor-
able conformation for binding. But, because the affinity
of 3 is still lower than that of more conformationally
flexible N1-benzenesulfonyltryptamines (such as 6b), it
would seem that the ‘out-of-plane’ rotamers (i.e., those
where s is closer to 60° or 300°) might be preferred for
an optimal interaction with the receptor.
14. Glennon, R. A.; Schubert, E.; Jacyno, J. M. J. Med.
Chem. 1980, 23, 1222.
15. (a) Jasti, V.; Ramakrishna, V. S. N.; Kambhampati, R. S.;
Battula, S. R.; Veeraraeddy, A.; Rao, V. S. V. V. WO
2004/000849 A2, December 31, 2003; (b) Ramakrishna, V.
S. N.; Kambhampati, R. S.; Shirsath, V. S.; Jasti, V. WO
2005/005439 A1, January 20, 2005.
16. Human beings are not good at breaking with an
entrenched habit . . . even when logically we should be
able to see that this habit ought not be binding. Margolis,
H. It Started with Copernicus, McGraw Hill: New York,
2002, p. 120.
17. Glennon, R. A.; Bondarev, M.; Roth, B. L. Med. Chem.
Res. 1999, 9, 108.
18. Pullagurla, M. R.; Dukat, M.; Setola, V.; Roth, B.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2003, 13,
3355.
19. The h5-HT6 radioligand binding assay was performed as
previously described.20 In brief, h5-HT6 cDNA was
transiently expressed in HEK-293 cells using Fugene6
according to the manufacturer’s recommendations; 24 h
after transfection the medium was replaced, and 24 h later,
medium containing dialyzed serum (to remove 5-HT) was
added. At 72 h after transfection, cells were harvested by
scraping and centrifugation. Cells were then washed by
centrifugation and resuspension in phosphate-buffered
saline (pH 7.40, PBS) and frozen as tight pellets at
À80 °C until use. Binding assays were performed at room
temperature for 90 min in binding buffer (50 mM Tris–Cl,
10 mM MgCl2, and 0.1 mM EDTA, pH 7.40) with
[3H]LSD (1 nM final concentration) using 10 lM cloza-
pine for non-specific binding. Concentrations of unlabeled
test agent were used for Ki determinations with Ki values
calculated using the program GraphPad Prism (V4.0).
Specific binding represented 80–90% of total binding. Ki
values are the result of triplicate determinations.
20. Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.;
Huebner, K.; Lachowicz, J. E.; Meltzer, H. Y.; Sibley,
D. R.; Roth, B. L.; Hamblin, M. W. J. Neurochem. 1996,
66, 47.
Acknowledgment
The present work was supported in part by NIMH MH
60599.
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