S. Tasler et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6224–6229
6229
Table 6. Affinity data on other receptors
Acknowledgments
Discussions with and support by Drs. Daniel Vitt, Hajo
R
H
N
´
Peters, Javier Burguen˜o and Antonio Parraga were
highly appreciated. We sincerely thank Dr. Marta Pujol
for providing functional data.
N
N
References and notes
Receptor
R = CN
Ki [nM] (inhib. @ 1 lM)
R = PhSO2NH (19)
—(inhib. @ 1 lM)
1. For reviews, see: (a) Barnes, N. M.; Sharp, T. Neurophar-
macology 1999, 38, 1083; (b) Glennon, R. A. J. Med. Chem.
2003, 46, 2795; (c) Wooley, M. L.; Marsden, C. A.; Fone,
K. C. F. CNS Neurol. Disord. Drug Targets 2004, 3, 59; (d)
Holenz, J.; Pauwels, P. J.; Diaz, J. L.; Merce, R.; Codony,
X.; Buschmann, H. Drug Discovery Today 2006, 11, 283.
2. Holenz, J.; Merce, R.; Diaz, J. L.; Guitart, X.; Codony, X.;
Dordal, A.; Romero, G.; Torrens, A.; Mas, J.; Andaluz, B.;
Hernandez, S.; Monroy, X.; Sanchez, E.; Hernandez, E.;
Perez, R.; Cubi, R.; Sanfeliu, O.; Buschmann, H. J. Med.
Chem. 2005, 48, 1781.
5-HT2A
5-HT2B
5-HT2C
5-HT7
H1
47
— (61%)
— (63%)
— (14%)
— (6%)
— (2%)
— (68%)
— (72%)
— (52%)
— (65%)
N-methylpiperazine from the 4- into the 5-position (Ta-
ble 5), affinities were quite low for all head groups
tested, except for the aniline of entry 37 with an Ki of
164 nM, which, however, possesses a certain potential
for displaying mutagenic effects in vivo.
3. Romero, G.; Sanchez, E.; Pujol, M.; Perez, P.; Codony, X.;
Holenz, J.; Buschmann, H.; Pauwels, P. J. Br. J. Pharmacol.
2006, 148, 1133.
4. For details on 4SCanÒ as developed at 4SC, see: Seifert, M.
H. J.; Wolf, K.; Vitt, D. Biosilico 2003, 1, 143; for a
pharmacophore alignment, compounds of a virtual library
are partitioned into fragments, an anchor fragment is
selected and aligned on the parent structure, for example,
ligand E-6837, and adjusted in a way that similar electro-
static and hydrophobic interaction possibilities become
superimposed (unlike a structural alignment, in which
similar parts of the molecules are superimposed). Next
fragment is then connected to the first one and again
adjusted for maximal interaction identities based on the
position chosen for the first fragment. Several permutations
of starting fragments are evaluated, resulting in a pharma-
cophore alignment of maximal similarities in interaction
possibilities.
5. (a) Bromidge, S. M.; Clarke, S. E.; King, F. D.; Lovell, P.
J.; Newman, H.; Riley, G.; Routledge, C.; Serafinowska, H.
T.; Smith, D. R.; Thomas, D. R. Bioorg. Med. Chem. Lett.
2002, 12, 1357; (b) Bromidge, S. M.; Clarke, S. E.; Gager,
T.; Griffith, G.; Jeffrey, P.; Jennings, A. J.; Joiner, G. F.;
King, F. D.; Lovell, P. J.; Moss, S. F.; Newman, H.; Riley,
G.; Rogers, D.; Routledge, C.; Serafinowska, H. T.; Smith,
D. R. Bioorg. Med. Chem. Lett. 2001, 11, 55; (c) Bo¨s, M.;
Sleight, A. J.; Godel, T.; Martin, J. R.; Riemer, C.; Stadler,
H. Eur. J. Med. Chem. 2001, 36, 165.
6. Affinity of compounds at 5-HT6 receptors was evaluated
utilizing membranes from HEK-293 cells with human 5-
HT6 serotonin receptor expressed and the radioligand [3H]-
LSD according to Roth, B. L.; Craigo, S. C.; Choudhary,
M. S.; Uluer, A.; Monsma, F. J., Jr.; Shen, Y.; Meltzer, H.
Y.; Sibley, D. R. J. Pharmacol. Exp. Ther. 1994, 268, 1403.
7. Functional effects of the compounds were evaluated by
cAMP measurements on HEK-293F cells stably expressing
the human 5-HT6 receptor using a HTRF assay format
according to Romero, G.; Pujol, M.; Perez, P.; Buschmann,
H.; Pauwels, P. J. J. Pharmacol. Toxicol. Methods 2007, 55,
144, and see Ref. 3.
As already observed for nitroarene 1 (Fig. 1 and Table 1,
entry 1, R = Me), most other compounds tested for func-
tionality were found to be partial agonists at the 5-HT6
receptor as well (marked in Tables 1–4). In contrast, the
benzylamino-nitroarenes of Table 1, entries 3 and 4,
R = H displayed full agonism. Further investigations
are currently being made to explore potential correlations
of the magnitude of the agonistic effect with substitution
patterns within this structural class of 5-HT6 ligands.
For sulfonamide 19 and the 2-benzylaminobenzonitrile of
entry 29 being identified as new lead structures for further
structural evaluations (Kis around or below 100 nM),
some selectivity data was acquired (Table 6). Both com-
pounds displayed no selectivity issues at a compound con-
centration of 1 lM at 5-HT2B, 5-HT2C, 5-HT7, and H1-
receptors, which was also true at 5-HT2A for compound
19. The benzonitrile showed good affinity toward the lat-
ter (Ki below 100 nM), selectivity of which has hence to be
addressed in further synthetic endeavors.
In summary, a highly potent class of 5-HT6 ligands was
identified using the 4SCanÒ in silico technology, with
activities down to a Ki of 8 nM for nitroarenes and
108 and 60 nM for a benzonitrile and a phenylsulfona-
mide, respectively. Some SAR trends have been identi-
fied, a conclusive and elaborated analysis should better
be performed by computational methods (CoMFA
model), though, which will be published in due course.
Highly intriguing variants within this structural class
to be further explored would be diarylethers like the
one in Table 3, entry 26, with different substitution pat-
terns at the aryloxy substituent combined with other
head groups like nitrile, phenylsulfonamide, or benzyl-
oxy, which are still under investigation.
8. Tasler, S.; Mies, J.; Lang, M. Adv. Synth. Catal., in press.
9. McKillop, A.; Tarbin, J. A. Tetrahedron 1987, 43, 1753.